Perfluoro sulfonyl halides and related species as polymer support modifiers

ABSTRACT

Activated Supports, support-bound activators, strongly acidic supports, and silylating supports are provided; the activated support having the formula (I) wherein L is a linking group component; X is F, CL, OH, and trisubstituted silyloxy; and the shaded circle represents a solid or semi-solid support. Methods of using the activated supports in solid phase organic sync) thesis are also provided.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication No. 60/261,525 filed Jan. 12, 2001.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

[0002] Not applicable

BACKGROUND OF THE INVENTION

[0003] The present invention relates to the field of linking groups oractivators that are useful in the solid-phase preparation of singlecompounds and libraries, as well as methods that employ such linkinggroups and activators. The present invention also relates generally tothe use of activated supports and their use in organic solution phasechemistry and as derivatizing agents to aid in chromatography.

[0004] Solid phase synthesis has attracted considerable attention fromthe scientific community, and in particular, the pharmaceutical andagricultural research communities in an effort to speed up the discoveryof new biologically active compounds. Critical to the solid phasesynthesis of such compounds are the means to attach (and subsequentlyremove) the compounds from a support. The most frequently used linkersare acid-labile and photo-labile linkers which typically result in thecleaved product having a residual functional group (e.g., carboxylicacid, amide, amine or hydroxy group). Recently, the term “tracelesslinker” has been used to describe a strategy of releasing compounds froma solid support with little or no trace of the original point ofattachment. See James, Tetrahedron Lett., 1999, 55, 4855; Andres, etal., Curr. Opin. Chem. Biol., 1998, 2, 353; Reitz, Curr. Opin. DrugDiscovery Dev., 1999; 2, 358; and Zaragoza, Angew. Chem., Int. Ed. 2000,39, 2077.

[0005] What is needed in the art are polymer support-linker species thatactivate certain molecules toward other transformations that would beuseful in the preparation of single compounds or compound libraries, andthat can also act as traceless linkers.

[0006] NAFION™ (Dupont, Wilmington, Del.) is a perfluororesinsulfonicacid that could, in principle be used as a traceless linker insolid-phase organic synthesis. However, the inability to utilize NAFION™resin in high yields and conversions in solid phase organic synthesisapplications has been noted. See Akhtar, et al., Tetrahedron Lett. 2000,41, 4487; Liu, et al., Tetrahedron Lett. 2000, 41, 4493. Suchlimitations include the inability to be wetted or swollen by mostaprotic organic solvents. Thus, although NAFION™ is robust andchemically resilient, it is not useful in solid-phase organic synthesisbecause the perfluoropolymer side chains are not solvated. As a result,there is a need in the art for a polymer-supported perfluorosulfonatethat is swellable and wettable by most common solvents.

[0007] In addition to being used for solid phase organic synthesis,solid and semi-solid supports are also used in solution phase organicchemistry as catalysts or reagents. For example, in the field ofcatalysis and organic chemistry, there is widespread use of highlyacidic catalysts to promote chemical transformations. These often takethe form of polymer supported acids, which can be readily filtered awayfrom a reaction mixture at the completion of the reaction. Resins knownto those skilled in the art include polystyrene-based resins, controlledpore glass beads, NAFION™, polyethylene glycol resins, TENTAGEL™ (RappPolymere GmbH, Tubingen, Germany), and the like. See Olah, Synthesis1986, 7, 513. Whereas ion-exchange resins, and in particular cationexchange resins, are polymer-supported acids, they are typically basedon phenylsulfonic acids and are hence limited in acidity.Perfluorosulfonic acids are dramatically more acidic than phenylsulfonicacids and as such, are quite distinct and often capable of catalyzing abroader range of chemical transformations. Thus, there is a general needin the art for polymer-supported perfluorosulfonic acids and relatedderivatives.

[0008] Processes for making perfluorosulfonic solid acids viaencapsulation of perfluorosulfonic acids into hydrocarbon resins havebeen disclosed in WO 98/30521, however, these are not expected to findapplication in the field of solid phase organic synthesis because theperfluorosulfonate groups are not covalently bound to the resin.

[0009] NAFION™ has been demonstrated to act as a highly acidic supportedcatalyst. Its properties have been noted by Olah, Synthesis 1986, 7,513; Yamoto, Recent Res. Devel. In Pure & Applied Chem. 1998, 2, 297;Harmer, Adv. Mater. 1998, 10, 1255. However, NAFION™ and relatedpolymers in the art are not effectively swollen by most aprotic organicsolvents. Because NAFION™ is not swellable or wettable by most commonorganic solvents, only the acid groups on the surface of NAFION™ areavailable for reaction, while the majority of the acid groups containedwithin the polymer are unavailable for reaction. One technique ofincreasing the effective surface area is to grind the polymer into fineparticles and to imbed these into an inert carrier such as clay oramorphous silica. See Harmer, Adv. Mater. 1998, 10, 1255. These hybridmaterials are subject to leaching artifacts and can often be difficultto filter away due to the heterogeneity of the particles. Thus, there isa need in the art for supported superacids that are swollen by commonorganic solvents, allowing supported superacids to be used for moreapplications and under milder reaction conditions. See Ishihara, et al.,Angew. Chem. Int. Ed. 2001, 40.

[0010] A superacid polymer-supported resin that is swellable would behighly desirable due to the ease of use, the enhanced effective acidcontent (because most or all of the contained acid groups would beavailable for use), and compatibility with a wide range of solvents.

SUMMARY OF THE INVENTION

[0011] The present invention provides a variety of support-boundmoieties and activated supports, that have utility in solid phase orsolution phase synthesis, biosynthesis, catalysis, purification,analysis, and identification and screening. Each moiety and activatedsupport includes an activator portion that serves as a reactive centerand a linking group component that serves to provide a robust linkagebetween the support and the activator portion. The linking groupcomponents further include an activator enhancing portion that serves toincrease the reactivity of the activator portion and suitable spacerthat provides sufficient distance between the activator portion and thesupport.

[0012] In one aspect, the present invention provides a support-boundactivator having the formula:

[0013] wherein L is a linking group component; X is a member selectedfrom the group consisting of F, Cl, OH, and trisubstituted silyloxy;wherein the support-bound activator is covalently attached to a solid orsemi-solid support.

[0014] In another aspect, the present invention provides an activatedsupport comprising a solid or semi-solid support; and at least onesupport-bound activator having the formula:

[0015] wherein L is a linking group component; X is a member selectedfrom the group consisting of F, Cl, OH, and trisubstituted silyloxy; andwherein the support-bound activator is covalently attached to the solidor semi-solid support.

[0016] In another aspect, the present invention provides asupport-activated target comprising a solid or semi-solid support; anactivating group covalently attached to the solid or semi-solid support,wherein the activating group has the formula:

[0017] wherein L is an linking group component; and a target groupcovalently attached to the solid or semi-solid support; wherein thetarget group can be cleaved from the activating group by a nucleophile.

[0018] In another aspect, the present invention provides a library ofsupport-activated targets comprising a plurality of support-activatedtarget members, wherein each support-activated target member furthercomprises a solid or semi-solid support; an activating group covalentlyattached to the solid or semi-solid support, wherein the activatinggroup has the formula:

[0019] wherein L is an linking group component; and a target groupcovalently attached to the activating group; wherein the target group ofat least one support-activated target member in the library is differentfrom the target group of at least one other support-activated targetmember in the library.

[0020] In another aspect, the present invention provides a stronglyacidic support comprising a solid or semi-solid support; and at leastone support-bound strongly acid group having the formula:

[0021] wherein L is a linking group component; and X is OH; and whereinthe support-bound strongly acid group is covalently attached to thesolid or semi-solid support.

[0022] In another aspect, the present invention provides a silylatingsupport comprising a solid or semi-solid support; and at least onesupport-bound silylating group having the formula:

[0023] wherein L is a linking group component; X is a trisubstitutedsilyloxy; wherein the support-bound silylating group is covalentlyattached to the solid or semi-solid support.

[0024] In yet another aspect, the present invention provides a methodfor covalently attaching a nucleophile to a compound having a hydroxygroup or an enolizable ketone, the method comprising,

[0025] (a) contacting a compound having a hydroxy group or an enolizableketone with a support-bound activator, wherein said contacting acompound having a hydroxy group or an enolizable ketone with a supportbound activator forms an activated complex; and

[0026] (b) contacting the activated complex with a reagent comprising anucleophile under conditions sufficient to covalently attach thenucleophile to the compound.

[0027] In still another aspect, the present invention provides a linkerreagent having the formula:

[0028] wherein L is a linking group component; and A is an attachinggroup.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG. 1 illustrates a synthetic scheme for the preparation of asupport-bound perfluorosulfonyl fluoride linker in accordance with thepresent invention.

[0030] FIG. 2 illustrates a synthetic scheme for the preparation of asupport-bound perfluorosulfonic acid in accordance with the presentinvention.

[0031] FIG. 3 illustrates a synthetic scheme for the deoxygenationreaction sequence for phenols to generate the parent arenes inaccordance with the present invention.

[0032] FIG. 4 illustrates a synthetic scheme to effect a cleavage/crosscoupling reaction to afford biaryls in accordance with the presentinvention

[0033] FIG. 5 illustrates a synthetic scheme whereby a library oftargets are prepared on the polymer support in accordance with thepresent invention.

[0034] FIG. 6 illustrates the synthesis of a known drug substance andsubsequent cleavage from the polymer support in accordance with thepresent invention.

[0035] FIG. 7 illustrates the preparation of a perfluorosulfonic acidpolymer in accordance with the present invention.

DETAILED DESCRIPTION OF THE INVENTION

[0036] In accordance with the present invention and as used herein, thefollowing terms and abbreviations are defined with the followingmeanings, unless explicitly stated otherwise. These explanations areintended to be exemplary only. They are not intended to limit the termsas they are described or referred to throughout the specification.Rather these explanations are meant to include any additional aspectsand/or examples of the terms as described and claimed herein.

[0037] The following abbreviations are used herein: AcOH or HOAc, aceticacid; Boc, t-butoxycarbonyl; DMF, dimethylformamide; EtOAc, ethylacetate; NMP, N-methylpyrrolidone; TFA, trifluoroacetic acid.

[0038] The term “support-bound activator” as used herein refers to anactivator which is attached to a solid or semi-solid support by at leastone covalent bond. The term “activator” as used herein refers to achemical moiety which activates, or increases the chemical reactivityof, another portion of a molecule. The term “support-bound activator” isnot meant to limit the location of the support-bound activator on thesolid or semi-solid support; that is, the support-bound activator can becovalently attached to the surface portion of the solid or semi-solidsupport or the support-bound activator can be covalently attached to anyinternal portion of the solid or semi-solid support. In other words, thesupport-bound activator can be covalently attached to any portion of thesolid or semi-solid support.

[0039] The term “activator portion” as used herein refers to the portionof an activator that increases the chemical reactivity of the activator.In a preferred embodiment, an activator portion comprises the moiety(—CF₂—SO₂—X). Activator portions may have analogous counterparts knownin the art of solution phase chemistry.

[0040] The term “linking group component” as used herein means a moietythat links together a plurality of other moieties. Thus, in oneembodiment of the present invention, one portion of a linking groupcomponent in a surface-bound activator will have at least one covalentbond with the solid or semi-solid support, and another portion of thelinking group component will have at least one covalent bond with anactivator portion. Furthermore, the linking group component of asurface-bound activator may have a covalent bond with a plurality ofactivator portions. Preferably, the linking group component providessuitable spacing for the activator portion to interact with moleculesexposed to the activator. The linking group component is preferably 6-50atoms long, more preferably 8-40 atoms long, even more preferably 8-30atoms long, and yet more preferably 8-20 atoms long. Additionally, thelinker reagent, prior to reaction with the solid or semi-solid support,will include a linking group component; this linking group componentwill have one portion that has at least one covalent bond with anattaching group and another portion with at least one covalent bond withan activator portion. The term “attaching group” as used herein refersto that portion of a linker reagent that can form a covalent bond withthe solid or semi-solid support.

[0041] The term “activator enhancing portion” as used herein refers tothat portion of the linking group component that increases the chemicalreactivity of the activator portion of a support-bound activator. Anactivator enhancing portion may also extend the length of the linkergroup component, and additionally, effect the motility of thesurface-bound activator.

[0042] The terms “solid” or “semi-solid support” as used herein refersto any form of a polymer or composite material that does not completelydissolve in a solvent. By way of example only, a solid or semi-solidsupport includes colloids (isolated or in suspension), gels, resins,films, as well as any other form of a polymer or composite materialsthat retains a distinct identity apart from the solvent. The term is notmeant to limit in any manner the size, shape, form, or chemicalstructure of the polymeric or composite material. Such polymeric orcomposite materials are well known in the art, including, by way ofexample only, cellulose, pore-glass, silica, polystyrene, polystyrenecross-linked with divinylbenzene, polyacrylamide, latex,dimethylacrylamide, dimethylacrylamide cross-linked withN,N′-bis-acryloyl ethylene diamine, glass, glass coated with ahydrophobic polymer, composites, or any other material conventionallyused in solid phase organic synthesis. A valuable reference in thisregard is the Novabiochem 2000 catalog, which is incorporated herein byreference. In addition, the term solid or semi-solid support is notlimited by the presence and nature of cross-linking groups, and by thenature of the exposed functional groups. Exposed functional groups aremoieties on the solid or semi-solid support that can react with linkerreagents to form support-bound activators; preferred exposed functionalgroups include —OH, —SH, —NH₂, silyloxy, NHR, NH₂NH, CO₂H, CO₂R, C(O)H,—Br, —I, halomethyl, and alkenyl. Furthermore, the exposed functionalgroups can be located on the surface of the solid or semi-solid supportor dispersed throughout the solid or semi-solid support. In oneembodiment, the solid or semi-solid support has a rigid or semi-rigidsurface.

[0043] The term “particulate support” as used herein refers to a type ofsolid or semi-solid support that is in the form of small particles. Theterm is not meant to limit the shape of the solid or semi-solid support.Thus, by way of example only, a particulate support can be a sphere,disk, pellet, sheet, plug, pin, crown, lantern, capillary, hollow fiber,needle, solid fiber, in a beaded or non-beaded form, a resin, a gel, amicrosphere, an amorphous shape, or any other conventional form. As oneskilled in the art will readily recognize, the scope of the presentinvention is not limited to the form or shape of the particulatesupport. The term “particulate support” is not meant to limit thechemical structure of the solid or semi-solid support, and can becomposed of any polymer, composite, cross-linker, if any, and exposedfunctional group. Thus, by way of example only, a particulate supportcan be composed of cellulose, pore-glass, silica, polystyrene,polystyrene cross-linked with divinylbenzene, polyacrylamide, latex,dimethylacrylamide, dimethylacrylamide cross-linked withN,N′-bis-acryloyl ethylene diamine, glass, glass coated with ahydrophobic polymer, composites, or any other material conventionallyused in solid phase organic synthesis. A valuable reference in thisregard is the Novabiochem 2000 catalog, which is incorporated herein byreference. A particulate support may also be porous, deformable, hard,wettable, or swellable. The particles will generally be at least 20micron, preferably at least 75 micron, and more preferably at least 100micron in diameter. A particulate support will generally maintain itsmechanical integrity during use, have functional groups that can reactwith active species, allow for the serial synthesis of attached targets,can be readily mixed and separated, and will allow for convenientdetachment of tags and products. The solid or semi-solid supports may beused as single particle, as groups of particles, as free flowingparticles, and may be packed into columns, tubes or other flow-throughdevices.

[0044] The term “resin” as used herein refers to any of a class of solidor semi-solid organic products of natural or synthetic origin, generallyof high molecular weight with no definite melting point. A resin may bechemically inert toward reagents and solvents used in solid phasesyntheses or may be functionalized with reactive moieties. Resins mayswell extensively in solvents.

[0045] The term “gel” as used herein refers to a colloidal suspension ofa liquid in a solid, forming a jellylike material having properties ofboth solid and a solution.

[0046] The term “colloid” as used herein a substance consisting of verytiny particles suspended in a continuous medium, such as a liquid, asolid, or a gaseous substance. Generally, the diameter of a colloidalparticle is from 20 nm to 200 micron, more preferably 100 nm to 200micron, even more preferably 500 nm to 200 micron, and yet even morepreferably 1 micron to 200 micron.

[0047] The term “microsphere” as used herein refers to any materialwhich is roughly spherical in shape. Microspheres may be processed,machined, milled, ground, or extruded according to processes known inthe art.

[0048] The term “superacid” as used herein is a solution of a strongacid in a very acidic solvent. A superacid is an acid that exhibitsstrength greater than that of 100% H₂SO₄.

[0049] The term “controlled pore glass” as used herein refers to a glassused as an inorganic support. Controlled pore glass is produced from aborosilicate base material which is heated to separate the borates andthe silicates. The borates are leached out from the material, leavingthe silica glass with uniform, controlled pores. Controlled pore glasseshave excellent mechanical properties, and can be prepared with a widerange of porosities and average pore sizes. They can be modified toinclude a variety of functional groups.

[0050] The term “polyacrylamide” or PAM as used herein refers to asynthetic water-soluble polymer made from monomers of acrylamide. PAMmay be fashioned into gels having a variety of pore sizes.

[0051] The term “polyethylene glycol” or “PEG” as used herein refers toa water-soluble, waxy polymer comprising subunits HO—(CH₂CH₂O)_(n)H. Theterm “poly(ethyleneglycol)monomethyl ether” as used herein refers toCH₃O(CH₂CH₂O)_(n)H and may be referred to as methyl-capped PEG. Askilled artisan will recognize that other capped PEGs may be employedwithout departing from the spirit of the invention.

[0052] The term “silica gel” as used herein refers to silicic acid orprecipitated silica. Silica gel is an amorphous powder insoluble inwater and organic solvents. Silica gel can adsorb up to about 40% of itsweight in moisture.

[0053] The term “cellulose” as used herein refers to one of manypolymers found in nature, as for example in wood, paper, and cotton.Cellulose is a polysaccharide and comprises repeating units of themonomer glucose. Cellulose may be crosslinked and derivatized, e.g., asin methylcellulose.

[0054] The term “acrylic acid grafted polypropylene” as used hereinrefers to a material comprising a polypropylene backbone andpolyacrylate, e.g. acrylic acid side chains. One process modifying theproperties of polyolefins comprises the “grafting” of polar monomersonto the polyolefin.

[0055] The term “target group” as used herein refers to a moietycovalently bound to a support-bound activator. According to oneembodiment of the present invention, a support-bound target comprises atarget group covalently attached to support as disclosed herein.

[0056] The term “cleaved from” as used herein refers to a plurality oftransformations disclosed herein in which a target group is removed froman activated support. According to one embodiment of the invention, asupport-bound target group is cleaved from or released from asupport-bound activator.

[0057] The term “polystyrene support” as used herein refers topolymerized monomers of styrene. A polystyrene support may take the formof beads as described herein. A polystyrene support may comprise across-linked copolymer of styrene and divinyl benzene.

[0058] The term “polystyrene modified by polyethylene glycol” as usedherein refers to a polystyrene polymer or cross-linked polystyrenepolymer grafted with ethylene glycol monomer or ethyleneglycol polymer(EG). An example of a polystyrene modified by polyethylene glycol isTENTAGEL™ resin.

[0059] The term “grafted” as used herein refers to a process whereinmonomers or polymers are covalently bonded to an existing polymer.

[0060] The term “TENTAGEL™” as used herein refers to a family of graftedcopolymers consisting of a low crosslinked polystyrene matrix on whichpolyethyleneglycol (PEG) is grafted. Because PEG is a polymer with bothhydrophobic and hydrophilic properties, the graft copolymer showsmodified physico-chemical properties. A TENTAGEL™ resin may compriseabout 50-70% PEG (w/w). Therefore, many chemical and physical propertiesof these polymers are highly dominated by the properties of PEG and notby the hydrophobic polystyrene support. Other related members of thisfamily, for the purpose of this invention, include ARGOGEL™ resin(Argonaut Technologies, Foster City, Calif.), ARGOPORE™ resin (ArgonautTechnologies, Foster City, Calif.), HYPOGEL™ resin (Rapp Polymere GmbH,Tubingen, Germany), and JANDAJEL™ resin (Scripps Research Institute, LaJolla, Calif.).

[0061] The term “protecting group” as used herein, refers to any of thegroups which are designed to block one reactive site in a molecule ormoiety while a chemical reaction is carried out at another reactivesite. More particularly, the protecting groups used herein can be any ofthose groups described in Greene, et al., Protective Groups In OrganicChemistry, 2nd Ed., John Wiley & Sons, New York, N.Y., 1991, which isincorporated herein by reference. The proper selection of protectinggroups for a particular synthesis will be governed by the overallmethods employed in the synthesis and such practice is well known tothose skilled in the art. The term “protected forms thereof” as usedherein refers to a moiety to which a protecting group has been attached.

[0062] The term “unsubstituted” refers to molecules or moieties that donot have additional moieties attached to the named group other than theroot compound. Thus, an unsubstituted (C₁-C₈)alkyl group consists onlyof from 1 to 8 alkyl carbon atoms with attached hydrogens.

[0063] The term “optionally substituted” or “substituted” refers tomolecules or moieties substituted by one to four substituents,independently selected from lower alkyl, lower aryl, lower aralkyl,lower alicyclic, hydroxy, lower alkoxy, lower aryloxy, perhaloalkoxy,aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy,azido, amino, guanidino, halo, lower alkylthio, oxo, acylalkyl, carboxyesters, carboxyl, carboxamido, nitro, acyloxy, aminoalkyl,alkylaminoaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino,phosphono, sulfonyl, carboxamidoalkylaryl, carboxamidoaryl,hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy, aminocarboxamidoalkyl,cyano, lower alkoxyalkyl, lower perhaloalkyl, and arylalkyloxyalkyl.

[0064] The term “lower” referred to herein in connection with organicradicals or compounds respectively defines such as with up to andincluding 10 carbon atoms, preferably up to and including 6 carbonatoms, and advantageously one to four carbon atoms. Such groups may bestraight chain, branched, or cyclic.

[0065] The term “alkyl” refers to a saturated hydrocarbon radical whichmay be straight-chain (for example, methyl, ethyl, propyl or butyl) orbranched-chain (for example, isopropyl, t-amyl, or 2,5-dimethylhexyl) orcyclic (for example, cyclobutyl, cyclopropyl or cyclopentyl). Thisdefinition applies both when the term is used alone and when it is usedas part of a compound term, such as “aralkyl” and similar terms.Preferred alkyl groups are those containing from 1 to 8 carbon atoms,and are referred to as a “(C₁-C₈)alkyl” group. Other preferred alkylgroups include those containing from 1 to 20 carbon atoms. All numericalranges in this specification and claims are intended to be inclusive oftheir upper and lower limits. The alkyl group may be optionallysubstituted.

[0066] The term “alkylene” as used herein refers to a divalent carbonmoiety, e.g., CR₂. Alkylene groups be linked to form straight chainalkyl groups and may be optionally substituted with up to twosubstituents per carbon atom.

[0067] The term “alkenyl” as used herein refers to a moiety whichcontains one or more sites of unsaturation. The term “alkenyl” as usedherein may also refer to a moiety which contains at least onecarbon-carbon double bond and includes straight-chain, branched-chainand cyclic groups. Alkenyl groups may be optionally substituted. Theterms “vinyl” and “olefinic” are sometimes used interchangebly with theterm alkenyl.

[0068] The term “(C₁-C₈)alkenyl” as used herein refers to an alkenylgroup having from 1 to 8 carbon atoms. Such groups may be straightchain, branched, or cyclic. A (C₁-C₈)alkenyl group may be optionallysubstituted.

[0069] The term “alkynyl” as used herein refers to a moiety thatcontains at least one carbon-carbon triple bond and includesstraight-chain, branched-chain and cyclic groups. Alkynyl groups may beoptionally substituted.

[0070] The term “(C₁-C₈ )alkynyl” as used herein refers to an alkynylgroup having from 1 to 8 carbon atoms. Such groups maybe straight chain,branched, or cyclic. A (C₁-C₈)alkynyl group may be optionallysubstituted.

[0071] The term “aryl” as used herein refers to a moiety having either asingle ring or multiple rings which are fused together and which has atleast one ring having a conjugated pi electron system; the multiplesrings may also be linked covalently or via a common group such as anethylene or methylene moiety. Aryl groups may be optionally substitutedat any position on the ring which would otherwise be occupied by ahydrogen atom.

[0072] The term “trisubstituted silyloxy” as used herein refers to amoiety having the formula —OSiR³R⁴R⁵, wherein, each of R³, R⁴, and R⁵ isindependently a member selected from the group consisting of substituted(C₁-C₈)alkyl, unsubstituted (C₁-C₈)alkyl, substituted (C₁-C₈)alkenyl ,unsubstituted (C₁-C₈) alkenyl, substituted aryl, and unsubstituted aryl.

[0073] The term “heteroalkyl” refers to an alkyl radical or group inwhich 1, 2, or 3 of the carbon atoms in the main chain of atoms has beenreplaced by a heteroatom selected from oxygen, nitrogen, sulfur orsilicon. Thus, the term (C₂-C₈)heteroalkyl refers to a group having from2 to 8 main chain atoms, at least one of which is a heteroatom. Forexample, a C₃ heteroalkyl group is meant to include —CH₂OCH₃ (the oxygenatom taking the place of the central carbon atom in a C₃ alkyl propyl)group. A heteroalkyl may be optionally substituted.

[0074] The term “heteroaryl” as used herein refers to an aryl radicalhaving from 1 to 4 heteroatoms as ring atoms in the aromatic ring, withthe remainder of the ring atoms being carbon atoms. Suitable heteroatomsinclude oxygen, sulfur, and nitrogen. By way of example only, suitableheteroaryl groups include furanyl, thienyl, pyridyl, pyrrolyl, N-loweralkyl pyrrolyl, pyridyl-N-oxide, pyrimidyl, pyrazinyl, and imidazolyl. Aheteroaryl may be optionally substituted.

[0075] The term “biaryl” as used herein refers to an aryl radicalcontaining more than one aromatic ring including both fused ring systemsand aryl groups substituted with other aryl groups. By way of exampleonly, suitable biaryls include naphthyl and biphenyl. A biaryl may beoptionally substituted.

[0076] The term “alicyclic” as used herein refers to a moiety or acompound which combines the structural properties of aliphatic andcyclic or heterocyclic compounds and includes, but is not limited to,aromatic, cycloalkyl and bridged cycloalkyl compounds. An alicyclic maybe optionally substituted. By way of example only, suitable alicyclicsinclude cyclohexenylethyl and cyclohexylethyl are suitable alicyclicgroups.

[0077] The term “aralkyl” refers to an alkyl group substituted with anaryl group. Suitable aralkyl groups include benzyl, picolyl, and thelike, and may be optionally substituted.

[0078] The terms “arylamino” (a), and “aralkylamino” (b), respectively,refer to the group —NRR′ wherein respectively, (a) R is aryl and R′ ishydrogen, alkyl, aralkyl or aryl, and (b) R is aralkyl and R′ ishydrogen or aralkyl, aryl, alkyl.

[0079] The term “acyl” refers to —C(O)R where R is alkyl and aryl. Byway of example only, acyl radicals include acetyl, pentanoyl, benzoyl,4-hydroxybenzoyl, pivaloyl and 4-hydroxyphenylacetyl.

[0080] The term “carboxy esters” refers to —C(O)OR where R is alkyl,aryl, aralkyl, and alicyclic, all optionally substituted.

[0081] The term “carboxyl” refers to —C(O)OH.

[0082] The term “oxo” refers to ═ attached to carbon or hetero atom.

[0083] The term “amino” refers to —NRR′ where R and R′ are independentlyselected from hydrogen, alkyl, aryl, aralkyl and alicyclic, all except Hare optionally substituted; and R and R′ can form a cyclic ring system.

[0084] The term “halogen” or “halo” refers to —F, —Cl, —Br and —I.

[0085] The term “heterocyclic” and “heterocyclic alkyl” refer to cyclicgroups containing at least one heteroatom. Suitable heteroatoms includeoxygen, sulfur, and nitrogen. Heterocyclic groups may be attachedthrough a nitrogen or through a carbon atom in the ring. Suitableheterocyclic groups include pyrrolidinyl, morpholino, morpholinoethyl,and pyridyl.

[0086] The term “phosphono” refers to —PO₃R₂, where R is selected fromthe group consisting of —H, alkyl, aryl, aralkyl, and alicyclic.

[0087] The term “sulfonyl” refers to —SO₃R, where R is H, alkyl, aryl,aralkyl, and alicyclic.

[0088] The term “acyloxy” refers to the ester group —O—C(O)R, where R isH, alkyl, alkenyl, alkynyl, aryl, aralkyl, or alicyclic.

[0089] The term “hydroxy” refers to the OH group

[0090] The term “thiol” refers to the SH group.

[0091] The term “alkylamino” refers to an amine-NR₂ wherein at least oneR is an alkyl group.

[0092] The term “(C₁-C₈)alkylamino” refers to an alkylamino group havinga single alkyl group, wherein the alkyl group has up to and including 8carbon atoms. Suitable alkyl groups may be straight chain, branched, orcyclic and may be optionally substituted.

[0093] The term “dialkylamino” refers to an amine-NR₂ wherein both Rgroups are alkyl groups. Suitable alkyl groups may be straight chain,branched, or cyclic and may be optionally substituted.

[0094] The term “di(C₁-C₈)alkylamino” refers to an amine-NR₂ whereinboth R groups are alkyl groups. Suitable alkyl groups may be straightchain, branched, or cyclic and may be optionally substituted. Further,the two alkyl groups may be joined to form a ring comprising thenitrogen as a hetero atom.

[0095] The term “aminoalkyl-” refers to the group NR₂-alk- wherein “alk”is an alkylene group and R is selected from H, alkyl, aryl, aralkyl, andalicyclic.

[0096] The term “alkylaminoalkyl-” refers to the group alkyl-NR-alk-wherein “alk” is an alkylene group and R is H or lower alkyl. “Loweralkylaminoalkyl-” refers to groups where each alkyl group is loweralkyl.

[0097] The term “arylaminoalkyl-” refers to the group aryl-NR-alk-wherein “alk” is an alkylene and R is H, alkyl, aryl, aralkyl, andalicyclic. In “lower arylaminoalkyl-”, the alkyl group is lower alkyl.

[0098] The term “alkylaminoaryl-” refers to the group alkyl-NR-aryl-wherein “aryl” is a divalent group and R is H, alkyl, aralkyl, andalicyclic. In “lower alkylaminoaryl-”, the alkyl group is lower alkyl.

[0099] The term “alkyloxyaryl-” refers to the group alkyl-O-aryl-wherein an “aryl” is a divalent group. In “lower alkyloxyaryl-”, thealkyl group is lower alkyl.

[0100] The term “aryloxyalkyl-” refers to an alkylene group substitutedwith an aryloxy group.

[0101] The term “alkoxy” refers to an alkyl group as described abovewhich also bears an oxygen substituent which is capable of covalentattachment to another hydrocarbon radical (such as, for example,methoxy, ethoxy and t-butoxy).

[0102] The term (C₁-C₈)alkoxy as used herein refers to an alkoxy group,wherein alkyl is a (C₁-C₈)alkyl.

[0103] The term “alkenyloxy” as used herein refers to the group—O-alkenyl wherein “alkenyl” is an alkenyl group.

[0104] The term (C₁-C₈)alkenyloxy as used herein refers to alkenyloxy,wherein the alkenyl is a (C₁-C₈)alkenyl.

[0105] The term “aryloxy” as used herein refers to the group Ar-O—wherein “Ar” is an aryl group.

[0106] The terms “alkylthio-” as used herein refers to the groupalkyl-S—.

[0107] The term “(C₁-C₈)alkylthio” as used herein refers to the groupalkyl-S— wherein alkyl has up to and including 8 carbon atoms.

[0108] The terms “amido” or “carboxamido” as used herein refers toNR₂—C(O)— and RC(O)—NR¹—, where R and R¹ include H, alkyl, aryl,aralkyl, and alicyclic. The term does not include urea, —NR—C(O)—NR—.

[0109] The term “aminocarboxamidoalkyl-” as used herein refers to thegroup NR₂—C(O)—N(R)-alk- wherein R includes H, alkyl, aryl, aralkyl, andalicyclic, and “alk” is an alkylene group. “Loweraminocarboxamidoalkyl-” refers to such groups wherein “alk” is loweralkylene.

[0110] The term “heteroarylalkyl” refers to an alkyl group substitutedwith a heteroaryl group.

[0111] The term “perhalo” as used herein refers to groups wherein everyC—H bond has been replaced with a C-halo bond. Suitable perhaloalkylgroups include —CF₃ and —CFCl₂. Suitable perhaloalkylene groups include—CF₂ and mixed halogen species, e.g., —CFCl.

[0112] The term “cyano” or “nitrile” as used herein refers to a —C≡Ngroup.

[0113] The term “nitro” as used herein refers to a —NO₂ group.

[0114] The term “alkylsulfonyl” as used herein refers alkOS(O)₂— whereinalk is an alkyl.

[0115] The term “phosphonate” as used herein refers to the moietyP(═O)(OR)₂ wherein P(═O) designates a phosphorous oxo group, an whereinR may be an aliphatic group.

[0116] The term “ester” as used herein refers to a chemical moiety withformula —(R)_(n)COOR′, where R and R′ are independently selected fromthe group consisting of alkyl or aryl and n is 0 or 1.

[0117] The term “amide” as used herein refers to a chemical moiety withformula —(R)_(n)—CONHR′, where R and R′ are independently selected fromthe group consisting of alkyl or aryl and n is 0 or 1.

[0118] The term “imide” as used herein refers to a chemical moiety withformula —(R)_(n)—CONR₂′, where R and R′ are independently selected fromthe group consisting of alkyl or aryl and n is 0 or 1.

[0119] The term “cross-coupling” as used herein refers a reactionbetween an electrophile and a nucleophile resulting in the formation ofa new covalent carbon-carbon bond.

[0120] The term “organostannane” or “organostannane compound” as usedherein refers to a compound comprising at least one Sn—R chemical bond,wherein R is an organic moiety. Preferably R can be either an alkyl,alkenyl, aryl, heteroaryl, allyl or alkynyl moiety. Preferredorganostannanes are any which can engage in cross-coupling reactions.

[0121] The term “organozinc” or “organozinc compound” as used hereinrefers to a compound having at least one Zn—R chemical bond, wherein Ris an organic moiety. Preferably R can be either an alkyl, alkenyl,aryl, heteroaryl, allyl or alkynyl moiety. Preferred organozinccompounds according to the present invention are those which engage incross-coupling reactions.

[0122] The term “organoboron” or “organoboron compound” as used hereinrefers to a compound comprising at least one B—R chemical bond, whereinR is an organic moiety. Preferably R can be either an alkyl, alkenyl,aryl, heteroaryl, allyl or alkynyl moiety. Preferred organoborons arethose which engage in cross-coupling reactions.

[0123] The term “organoaluminum” or “organoaluminum compound” as usedherein refers to a compound comprising at least one Al—R chemical bond,wherein R is an organic moiety. Preferably R can be either an alkyl,alkenyl, aryl, heteroaryl, allyl or alkynyl moiety. Preferredorganoaluminums are those which engage in cross-coupling reactions.

[0124] The term “organomagnesium”, “organomagnesium compound”,“organomagnesium reagent” or “Grignard reagent” as used herein refers toa compound comprising at least one Mg—R chemical bond, wherein R is anorganic moiety. Preferably R can be either an alkyl, alkenyl, aryl,heteroaryl, allyl or alkynyl moiety. Preferred organomagnesium compoundsare those which engage in cross-coupling reactions

[0125] The term “organolithium” or “organolithium compound” as usedherein refers to a compound comprising at least one Li—R chemical bond,wherein R is an organic moiety. Preferably R can be either an alkyl,alkenyl, aryl, heteroaryl, allyl or alkynyl moiety.

[0126] The term “organosilicon” or “organosilicon reagent” as usedherein refers to a compound comprising at least one Si—R chemical bond,wherein R is an organic moiety. Preferably R can be either an alkyl,alkenyl, aryl, heteroaryl, allyl or alkynyl moiety.

[0127] The term “organocopper reagent” also know as “organocuprates” asused herein refers to a compound comprising at least one Cu—R chemicalbond, wherein R is an organic moiety. Preferably R can be either analkyl, alkenyl, aryl, heteroaryl, allyl or allynyl moiety.

[0128] The term dialkylphosphite, refers to compound having a formula:R₂P(═)OR′ wherein R and R′ comprise aliphatic or aryl groups. PreferablyR and R′ are independently selected from the group consisting of analkyl, alkenyl, aryl, heteroaryl, allyl or alkynyl moiety.

[0129] The term “aryl boronic acid” as used herein refers to compoundshaving a formula: ArB(OH)₂, wherein Ar refers to an aryl.

[0130] The term “metal halide” as used herein refers to any covalentlyor ionically bonded compound comprising at least one electropositiveelement and at least one electro-negative element. According to oneaspect of the present invention, a metal halide is a source of a halideanion.

[0131] The term “addition of a transition metal catalyst” refers to theuse of a transition metal catalyst to promote a desired chemicaltransformation. A transition metal catalyst comprises at least onetransition metal and associated ligands. A non-catalytic or poorlycatalytic transition metal can often be converted to a transition metalcatalyst by the addition of ligands into the reaction mixture; suchligands include, by way of example only, trialkylphosphines,triarylphosphines, and bis(diarylphosphino)L compounds, wherein L can bean alkylene, divalent aryl, divalent alkenyl, divalent alkynyl, divalentheteroalkyl, divalent heteroaryl, or a derivative of ferrocene. In oneset of embodiments, ligands include 1,3-bis(diphenylphosphino)propane or1,1′-bis(diphenylphosphanyl)ferrocene. Any particular transition metalcatalyst may have multiple ligands, not all of which need to beidentical. In one embodiment, the transition metal is palladium. The newcatalytically active species are also known as transition metalcomplexes. The skilled artisan will understand that the examplesprovided herein for transition metal catalyst, transition metal andligand are for illustrative purposes only and that the scope of thepresent invention is not limited by the identity of the transition metalcatalyst, the transition metal, and the ligands. The catalyst and theoptional ligand which together form a catalytically active species maybe used at levels close to 100% relative to the reacting species,preferably <25% relative to the reacting species, more preferably <10%relative to the reacting species.

[0132] The term “covalently attached” as used herein refers to thepresence of a covalent bond between two or more moieties.

[0133] The term “nucleophile” as used herein is a compound or moietythat is reactive towards an electrophile so as to form a covalentbetween the nucleophile and electrophile. The terms “nucleophile” and“electrophile” have their usual meanings familiar to synthetic and/orphysical organic chemistry. Carbon electrophiles typically comprise oneor more alkyl, alkenyl, alkynyl or aromatic carbon atom substituted withany atom or group having a Pauling electronegativity greater than thatof hydrogen. Examples of preferred carbon electrophiles include but arenot limited to carbonyls (especially aldehydes and ketones), oximes,hydrazones, epoxides, aziridines, alkyl-, alkenyl-, and aryl halides,acyls, sulfonates, and perhalosulfonates. Other examples of carbonelectrophiles include unsaturated carbons electronically conjugated withelectron-withdrawing groups, examples being the β-carbon inα,β-unsaturated ketones or carbon atoms in fluorine substituted arylgroups. The skilled artisan will realize that the scope of the inventionis not limited by the identity of the nucleophile.

[0134] The term “activated complex” as used herein refers to a moietythat is covalently bound to a surface-bound activator and which, as aresult, has an increased chemical reactivity relative to its parentcompound. According to one embodiment of the present invention an arylalcohol compound is converted into a more reactive, surface-boundaryloxy moiety, i.e., an activated complex, upon reaction with asurface-bound activator of the present invention.

[0135] The term “hydride” or “hydride reagent” as used herein, refers toproton that can act as a nucleophile. Examples of hydride reagentsfamiliar to the skilled artisan include but are not limited to NaBH₄,LiAlH₄, as well as any suitable transition-metal hydride. The hydridemay also be formed in situ, or during the course of the reaction, by aninteraction between one or more reagents. By way of example only, atransition metal-hydride is formed in situ in the presence of Pd(OAc)₂,ligand and formic acid, as described in Example 3 below.

[0136] The term “enolizable ketone” refers to any ketone bearing ahydrogen on an “alpha carbon” (the carbon atom once removed from thatbearing the oxo group), wherein said alpha proton may be readily removedby exogenous base or via intra molecular tautomerization:

[0137] The term “compound” as used herein refers to any identifiablemolecule.

[0138] The term “conditions” refers to factors that can affect theoutcome of a particular reaction and which can be controlled by theoperator performing the reaction or sequence of reactions. Examples ofsuch conditions include but are not limited to the length of time that aset of reagents is allowed to interact with a substrate, thetemperature, the solvent, the rates of addition of particular reagents,and the like. The skilled artisan will recognize that each particularset of reagents may have its own optimal set of “conditions”.

[0139] The term “conditions sufficient” as used herein refers to thoseconditions that are adequate to produce the results desired.

[0140] The term “contacting” as used herein refers to any processwhereby any reagent or combinations thereof is mixed, stirred, added to,shaken, dissolved, passed-over, passed through, another said reagentunder conditions such that two or more reagents can undergo a chemicalreaction or transformation.

[0141] The term “reagent” as used herein refers to any chemical compoundused alone or in combination with a different chemical compound toproduce a desired chemical reaction. The term “reagent” includes allcatalysts (transition metal based or otherwise), ligands, acids, basesand other materials that are added to a reaction mixture in order toprovide the desired result.

[0142] The term “moiety” as used herein refers to a specific portion ofa molecule, usually complex, that has a characteristic chemical orproperty or reactivity.

[0143] The term “linking group” as used herein refers to the entirechain of atoms liking an activator portion with a solid or semi-solidsupport.

[0144] General

[0145] The present invention provides a variety of reagents,particularly support-bound activators, that have utility in the area ofcombinatorial synthesis. Each reagent includes an activator portion thatserves as a reactive center and a linking group component that serves toprovide a robust linkage between the support and the activator portion.The linking group components further include an activator enhancingportion that serves to increase the reactivity of the activator portionand suitable spacer that provides sufficient distance between theactivator portion and the support. The present invention also providesfor activated supports on which construction of a target or library oftargets takes place; the targets can also be cleaved from the activatedsupport to liberate the desired compound from the activated support.

[0146] One important aspect of the present invention is the use of theactivated supports described herein as traceless linkers, as that termis understood by those skilled in the art. As described above, the term“traceless linker” has been used to describe a strategy of releasingcompounds from a solid support with little or no trace of the originalpoint of attachment. See James, Tetrahedron Lett., 1999, 55, 4855;Andres, et al., Curr. Opin. Chem. Biol., 1998, 2, 353; Reitz, Curr.Opin. Drug Discovery Dev., 1999, 2, 358; and Zaragoza, Angew. Chem.,Int. Ed. 2000, 39, 2077. As demonstrated in Examples 3, 4 and 5, and inTables 1, 2, and 3, the activated supports of the present invention willhave wide utility as traceless linkers in solid phase organic chemistry.As one skilled in the art will realize, these examples are merelyillustrative and the activated supports of the present invention arefully expected to act as traceless linkers in any reaction that cancleave a triflate-carbon bond.

[0147] In addition, any of the reactions described herein, as well asany reaction known in the art of organic chemistry that can retain theintegrity of a triflate-carbon bond, can be used to construct either atarget or a library of targets on the activated supports of the presentinvention. Accordingly a preferred aspect of the present invention is asupport-activated target group. In addition, another preferred aspect ofthe present invention is a library of support-activated target groups.

[0148] The support-bound activators or the present invention also serveto activate certain centers toward such reactions as reductions, Suzukicouplings, Stille couplings, Heck couplings, Buchwald reactions, COinsertions, CN insertions, carbon-sulfur bond formation, and others.

[0149] The use of triflates and nonaflates as precursors for aryl andvinyl cations has been widely recognized. See, for example, Ritter,Synthesis, 8:735-762 (1993). Briefly, an oxygen atom on an aryl or vinylgroup (e.g., as a phenol or an enolizable ketone) can be activated as atriflate ester (trifluoromethane sulfonate ester) or a related nonaflateester towards a subsequent reduction or cross-coupling that gives riseto a variety of substituted aromatic compounds or olefinic compounds.

[0150] It would be desirable to conduct the perfluorosulfonyl-directedtransformations on solid phase and take advantage of the versatilesynthetic transformations known for vinyl and aryl triflates (see,Ritter, ibid.). For example, the reductive cleavage of apolymer-supported aryl triflate could lead to deoxygenation of phenolswithout leaving a trace of the phenolic hydroxy group as a point ofattachment to the polymer, or resin. Wustrow and coworkers (TetrahedronLett. 39:3651 (1998)) reported the reductive cleavage of electron poorarylsulfonates from an ion-exchange resin based sulfonyl linker understringent cleavage conditions (140° C. for 12 h), but to date, therehave been no reports of polymer-supported triflates and nonaflates thatcould be used for activating hydroxy groups toward a variety ofsynthetic transformations.

[0151] NAFION™ resin is well known, yet suffers from having poorswelling properties and is difficult to activate. The inability ofNAFION™ to swell in the presence of common organic solvents prevents thevast majority of surface-bound reactive groups from reacting withcompounds in solution. As a result, NAFION™ has not found much utilityin solid-phase organic synthesis or in other uses that require more thana catalytic amount of available surface-bound reactive groups.

[0152] What is needed in the art are support-bound activators that haveimproved swelling properties and that are able to participate inperfluorosulfonate-based activation/displacement chemistry. Suchsupport-bound activators and the related activated supports are providedbelow.

[0153] The present invention also provides for strongly acidic supportswhich find application as catalysts or scavenger resins, particularlythose having increased swelling properties. In addition, the presentinvention provides for silylating supports which find application inanalytical chemistry or in other areas in which a silylated compound isdesired.

[0154] Description of the Embodiments

[0155] Support-Bound Activators

[0156] In one aspect, the present invention provides a support-boundactivator having the formula:

[0157] In formula I, the letter L represents a linking group component;the letter X represents F, Cl, trisubstituted silyloxy or OH. Thesupport-bound activator is attached to a solid or semi-solid support byat least one covalent bond.

[0158] Turning first to the solid or semi-solid support, the presentinvention is useful in a variety of solid-phase synthesis applicationsand, accordingly, a variety of supports find utility in this aspect ofthe invention. Typical solid supports include, but are not limited to,cross-linked divinylbenzene-styrene (polystyrene), controlled pore glass(CPG), polyacrylamides, poly(ethyleneglycol)monomethyl ether andpoly(ethylene glycol) (PEG), silica gel, cellulose, acrylic acid graftedpolypropylene, and the like. Additionally, the solid support contains areactive moiety suitable for attaching the linking group component.Suitably reactive moieties include, for example, a carboxylic acid,alcohol, amine, halomethyl and the like which is used to covalentlyattach the linking group component during construction of the presentsupport-bound activators. Many of these supports are available asfunctional polymers having reactive groups. Examples of such supports,include, by way of example, Acryloyl Wang resin, REM resin, Vinylpolystyrene, Vinylsulfonylmethyl polystyrene,(3-Formylindolyl)acetamidomethyl polystyrene,2-(3,5-Dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene,2-(4-Formyl-3-methoxyphenoxy)ethyl polystyrene,4-(4-Formyl-3-methoxyphenoxy)butyryl AM resin, 4-Benzyloxybenzaldehydepolystyrene, Aldehyde Wang resin, Formylpolystyrene, 1% DVB, NovaSyn® TGacetal resin, Polystyrene-CHO, Carboxypolystyrene, NovaSyn® TG carboxyresin, Polystyrene-COOH,4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxy resin,4-Methylbenzhydrylamine resin HCl, 4-Methylbenzhydrylamine resin HCl,9-Fmoc-amino-xanthen-3-yloxy, 9-Fmoc-amino-xanthen-3-yloxy,Amino-(4-methoxyphenyl)methyl polystyrene,Ethylamino-xanthen-3-yloxy-Merrifield resin, NovaSyn® TG Sieber resin,NovaSyn® TGR resin, Rink Amide AM resin, Rink Amide MBHA resin, Rinkamide NovaGel™, Rink amide PEGA resin, Rink Amide resin, Sieber Amideresin, Sieber Ethylamide resin, Amino methyl resin, Amino PEGA resin,Aminomethyl NovaGel™, Aminomethylated polystyrene, N-Methylaminomethylpolystyrene, 4-Fmoc-hydrazinobenzoyl AM resin, 1H-Benzotriazolepolystyrene, Benzotriazole-5-carbamidomethyl polystyrene,N-Fmoc-N-methoxy-β-alanine AM resin, Weinreb AM resin, 4-SulfamylbenzoylAM resin, (±)-1-(2,3-Isopropylidene)glycerol polystyrene,(±)-2,2-Dimethyldioxolan-4-methoxymethyl polystyrene, (±)-1-Glycerolpolystyrene, 4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-Hydroxymethyl-3-methoxyphenoxybutyric acid AM resin,4-Hydroxymethyl-3-methoxyphenoxybutyric acid BHA resin,4-Hydroxymethyl-3methoxyphenoxybutyric acid MBHA resin,4-Hydroxymethylphenoxyacetyl NovaGel™, 4-Hydroxymethylphenoxyacetyl PEGAresin, HMP resin, HMPA-NovaGel™, HMPB-AM resin, HMPB-BHA resin,HMPB-MBHA resin, Hydroxy-(2-chlorophenyl)methyl polystyrene,Hydroxymethylpolystyrene, NovaSyn® TG HMP resin, p-BenzyloxybenzylAlcohol resin, Polystyrene-CH₂OH, Rink Acid resin, TrichloroacetimidateWang resin, Wang resin, 4-Hydroxymethylbenzoic acid AM resin,4-Hydroxymethylbenzoic acid NovaGel™, 4-Hydroxymethylbenzoic acid PEGAresin, 4-Hydroxyphenylsulfanylmethyl polystyrene,9-(Hydroxymethyl)fluorene-4-carboxamidomethyl polystyrene, HESMpolystyrene, HMBA-AM resin, HMBA-NovaGel™, HMBA-PEGA resin,Hydroxyethylsulfanylmethyl polystyrene, NovaSyn® TG HMBA resin, NovaSyn®TG hydroxy resin, Oxime resin, Aminoethyl photolinker resin,Hydroxyethyl photolinker resins, Hydroxymethyl photolinker resins,3-[4-(Tritylmercapto)phenyl]propionyl AM resin, Mercaptomethylpolystyrene, NovaSyn® TG tritylthiol resin, Thiol 2-chlorotrityl resin,Thiol 4-methoxytrityl resin, (4-Bromophenyl)diisopropylsilyloxymethylpolystyrene, (4-Formylphenyl)diisopropylsilyloxymethyl polystyrene,(4-Trityloxyphenyl)diisopropylsilyloxymethyl polystyrene. Solid supportsalso include TENTAGEL™, HYPOGEL™, JANDAJEL™, AND ARGOGEL™. Other solidsupports include PEGylated polystyrene (polystyrene derivatized withpolyethylene glycol), Tentagel-NH₂ resin, and derivatized Tentagel-NH₂resin (e.g., by treatment with acetyl chloride followed by reductionwith LiAlH₄ to provide Tentagel-NHEt resin). See also the NovabiochemCatalogue 2000 for additional resins and immobilized functional groups.

[0159] Such supports may take any size, shape or form, includingparticulate and non-particulate forms or shapes, spheres, disks,pellets, sheets, plugs, pins, crowns, lanterns, in beaded and non-beadedforms, resins, gels, microspheres, as well as amorphous forms andshapes. Embodiments of particulate supports, include beads, pellets,disks, amorphous particles, or other conventional forms. The solid orsemi-solid supports may be used as single particle, as groups ofparticles, as free flowing particles, and may be packed into columns,tubes or other flow-through devices. In a one embodiment, the diameterof the particulate support is 20-2000 micron, preferably 75-500 micron,more preferably 100-200 micron. As one skilled in the art will readilyrecognize, the scope of the present invention is not limited to thesize, form, or shape of the solid or semi-solid support.

[0160] The linking group component can have a variety of structures. Thelinking group component is one which provides suitable spacing for theactivator portion (—CF₂—SO₂—X) to interact freely with molecules orreactive components exposed to the activator portion. The linking groupcomponent is preferably 6-50 atoms long, more preferably 8-40 atomslong, even more preferably 8-30 atoms long, and yet more preferably 8-20atoms long, thus providing sufficient exposure for the attachedactivator portion. Additionally, the linking group component, prior toattachment to the support, will have a attaching portion and a longerchain portion. The attaching portion is that part of the linking groupcomponent which can be directly attached to the solid support. Thisportion can be attached to the solid support via carbon-carbon bondsusing, for example, supports having exposed(poly)trifluorochloroethylene moieties, or preferably, by siloxane bonds(using, for example, glass or silicon oxide as the solid support).Siloxane bonds the support are formed in one embodiment via reactions ofattaching portions bearing trichlorosilyl or trialkoxysilyl groups. Theattaching groups will also have a site for attachment of the longerchain portion. For example, groups which are suitable for attachment toa longer chain portion would include amines, hydroxyl, thiol, andcarboxyl.

[0161] One skilled in the art will recognize that many additionalmethods of attaching linkers to solid and semi-solid supports exist. Onemethod uses an amino resin to which an acid-bearing linker is attachedvia conventional techniques. Another method is the use of aryl etherlinkages by coupling a phenol to a Merrifield (or equivalent) resin.

[0162] The longer chain portion can be any of a variety of moleculeswhich are inert to the subsequent conditions used in the activatorreactions described in further detail below. These longer chain portionscan be ethylene glycol oligomers containing 2-14 monomer units, or morepreferably 2-10 monomer units, and even more preferably 2-8 monomerunits; in addition, the longer chain portions can be diamines, diacids,amino acids, peptides, or combinations thereof. In some embodiments, thelonger chain portion also comprises an activator enhancing portion,i.e., a portion that increases the reactivity of the activator relativeto an alkylene or ethylene glycol linking group. More particularly, anactivator enhancing portion is one that provides additional electronwithdrawing character to the activator portion (e.g., the —CF₂—SO₂—Xportion).

[0163] In one group of embodiments, X is a member selected from thegroup consisting of F and Cl. In another group of embodiments, Lcomprises an activator enhancing portion selected from the groupconsisting of:

[0164] wherein Y is a member selected from the group consisting of achemical bond, O, CO, S, and NR¹; Z is a member selected from the groupconsisting of a chemical bond or CO; each R² is independently a memberselected from the group consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₁-C₈)alkoxy, (C₂-C₈)heteroalkyl, (C₁-C₈)alkylthio, (C₁-C₈)alkylamino,di(C₁-C₈)alkylamino, cyano, nitro and (C₁-C₈)alkylsulfonyl; thesubscript ‘g’ is an integer selected from the group consisting of 0, 1,2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscript ‘i’ is an integer selectedfrom the group consisting of 1, 2, 3, 4, 5, and 6; the subscript ‘j’ isan integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7,8, 9, and 10; the subscript ‘k’ is an integer selected from the groupconsisting of 1, 2, 3, and 4; the subscript ‘m’ is an integer selectedfrom the group consisting of 2 and 3; and the subscript ‘n’ is aninteger selected from the group consisting of 0, 1, 2, 3, and 4. In thegroups described herein as dialkylamino, the alkyl groups can be thesame or different, or can optionally be combined to form a ring havingadditional heteroatoms (e.g., pyrrolidino, morpholino, piperazino).

[0165] In another embodiment, the support-bound activator is availablein kit form for use in solid phase organic chemistry, as a reagent orcatalyst in solution phase organic chemistry, as a scavenger resin insolution phase organic chemistry, as a silylating agent for use inanalytical chemistry, and in particular, in chromatography, and as areagent for the production of PET-ready molecules.

[0166] In one group of of embodiments, the support-bound activators ofthe present invention are:

[0167] wherein the symbol R¹ and the subscripts g, i, j, k and m allhave the meanings provided above.

[0168] In another group of embodiments, the support-bound activatorshave a formula selected from:

[0169] In each of formulae A and B, X can be F, Cl, trisubstitutedsilyloxy, or OH; Q is O; Z is a chemical bond or C═O; Y is O-support orNR₁-support wherein R₁ is H, (C₁-C₈)alkyl or aryl and the support is aPEG-modified polystyrene or a Merrifield resin; and each R² is asdefined more generally above. The subscripts in formulae A and B are asfollows: ‘g’ is an integer selected from the group consisting of 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, and 11; ‘h’ is an integer selected from thegroup consisting of 1, 2, 3, 4, 5, 6, 7, and 8; ‘i’ is an integerselected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; ‘j’is an integer selected from the group consisting of 1, 2, 3, and 4; ‘k’is an integer selected from the group consisting of 1, 2, 3, and 4; ‘m’is an integer selected from the group consisting of 2 and 3; ‘n’ is aninteger selected from the group consisting of 0, 1, 2, 3, and 4; and ‘q’is an integer selected from the group consisting of 1, and 2.

[0170] In one particular embodiment in formulae A and B, X is F; Q is O;Z is C═O, Y is NH-support wherein the support is a PEG-modifiedpolystyrene; and each R² is H.

[0171] Activated Supports

[0172] In another aspect, the present invention provides an activatedsupport comprising a solid or semi-solid support; and at least onesupport-bound activator having the formula:

[0173] wherein L is a linking group component; X is a member selectedfrom the group consisting of F, Cl, OH, and trisubstituted silyloxy; andwherein the support-bound activator is covalently attached to the solidor semi-solid support.

[0174] Turning first to the solid or semi-solid support, the presentinvention is useful in a variety of solid-phase synthesis applicationsand, accordingly, a variety of supports find utility in this aspect ofthe invention. Typical solid supports include, but are not limited to,cross-linked divinylbenzene-styrene (polystyrene), controlled pore glass(CPG), polyacrylamides, poly(ethyleneglycol)monomethyl ether andpoly(ethylene glycol) (PEG), silica gel, cellulose, acrylic acid graftedpolypropylene, and the like. Additionally, the solid support contains areactive moiety suitable for attaching the linking group component.Suitably reactive moieties include, for example, a carboxylic acid,alcohol, amine, halomethyl and the like which is used to covalentlyattach the linking group component during construction of the presentsupport-bound activators. Many of these supports are available asfunctional polymers having reactive groups. Examples of such supports,include, by way of example, Acryloyl Wang resin, REM resin, Vinylpolystyrene, Vinylsulfonylmethyl polystyrene,(3-Formylindolyl)acetamidomethyl polystyrene,2-(3,5-Dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene,2-(4-Formyl-3-methoxyphenoxy)ethyl polystyrene,4-(4-Formyl-3-methoxyphenoxy)butyryl AM resin, 4-Benzyloxybenzaldehydepolystyrene, Aldehyde Wang resin, Formylpolystyrene, 1% DVB, NovaSyn® TGacetal resin, Polystyrene-CHO, Carboxypolystyrene, NovaSyn® TG carboxyresin, Polystyrene-COOH,4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxy resin,4-Methylbenzhydrylamine resin HCl, 4-Methylbenzhydrylamine resin HCl,9-Fmoc-amino-xanthen-3-yloxy, 9-Fmoc-amino-xanthen-3-yloxy,Amino-(4-methoxyphenyl)methyl polystyrene,Ethylamino-xanthen-3-yloxy-Merrifield resin, NovaSyn® TG Sieber resin,NovaSyn® TGR resin, Rink Amide AM resin, Rink Amide MBHA resin, Rinkamide NovaGel™, Rink amide PEGA resin, Rink Amide resin, Sieber Amideresin, Sieber Ethylamide resin, Amino methyl resin, Amino PEGA resin,Aminomethyl NovaGel™, Aminomethylated polystyrene, N-Methylaminomethylpolystyrene, 4-Fmoc-hydrazinobenzoyl AM resin, 1H-Benzotriazolepolystyrene, Benzotriazole-5-carbamidomethyl polystyrene,N-Fmoc-N-methoxy-β-alanine AM resin, Weinreb AM resin, 4-SulfamylbenzoylAM resin, (±)-1-(2,3-Isopropylidene)glycerol polystyrene,(±)-2,2-Dimethyldioxolan-4-methoxymethyl polystyrene, (±)-1-Glycerolpolystyrene, 4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-(2′,4′-Dimethoxyphenylhydroxymethyl)-phenoxy resin,4-Hydroxymethyl-3-methoxyphenoxybutyric acid AM resin,4-Hydroxymethyl-3-methoxyphenoxybutyric acid BHA resin,4-Hydroxymethyl-3-methoxyphenoxybutyric acid MBHA resin,4-Hydroxymethylphenoxyacetyl NovaGel™, 4-Hydroxymethylphenoxyacetyl PEGAresin, HMP resin, HMPA-NovaGel™, HMPB-AM resin, HMPB-BHA resin,HMPB-MBHA resin, Hydroxy-(2-chlorophenyl)methyl polystyrene,Hydroxymethylpolystyrene, NovaSyn® TG HMP resin, p-BenzyloxybenzylAlcohol resin, Polystyrene-CH₂OH, Rink Acid resin, TrichloroacetimidateWang resin, Wang resin, 4-Hydroxymethylbenzoic acid AM resin,4-Hydroxymethylbenzoic acid NovaGel™, 4-Hydroxymethylbenzoic acid PEGAresin, 4-Hydroxyphenylsulfanylmethyl polystyrene,9-(Hydroxymethyl)fluorene-4-carboxamidomethyl polystyrene, HESMpolystyrene, HMBA-AM resin, HMBA-NovaGel™, HMBA-PEGA resin,Hydroxyethylsulfanylmethyl polystyrene, NovaSyn® TG HMBA resin, NovaSyn®TG hydroxy resin, Oxime resin, Aminoethyl photolinker resin,Hydroxyethyl photolinker resins, Hydroxymethyl photolinker resins,3-[4-(Tritylmercapto)phenyl]propionyl AM resin, Mercaptomethylpolystyrene, NovaSyn® TG tritylthiol resin, Thiol 2-chlorotrityl resin,Thiol 4-methoxytrityl resin, (4-Bromophenyl)diisopropylsilyloxymethylpolystyrene, (4-Formylphenyl)diisopropylsilyloxymethyl polystyrene,(4-Trityloxyphenyl)diisopropylsilyloxymethyl polystyrene. Solid supportsalso include TENTAGEL™, HYPOGEL™, JANDAJEL™, AND ARGOGEL™. Other solidsupports include PEGylated polystyrene (polystyrene derivatized withpolyethylene glycol), Tentagel-NH₂ resin, and derivatized Tentagel-NH₂resin (e.g., by treatment with acetyl chloride followed by reductionwith LiAlH₄ to provide Tentagel-NHEt resin). See also the NovabiochemCatalogue 2000 for additional resins and immobilized functional groups.

[0175] Such supports may take any size, shape or form, includingparticulate and non-particulate forms or shapes, spheres, disks,pellets, sheets, plugs, pins, crowns, lanterns, in beaded and non-beadedforms, resins, gels, microspheres, as well as amorphous forms andshapes. Embodiments of particulate supports, include beads, pellets,disks, amorphous particles, or other conventional forms. The solid orsemi-solid supports may be used as single particle, as groups ofparticles, as free flowing particles, and may be packed into columns,tubes or other flow-through devices. In a one embodiment, the diameterof the particulate support is 20-2000 micron, preferably 75-500 micron,more preferably 100-200 micron. As one skilled in the art will readilyrecognize, the scope of the present invention is not limited to thesize, form, or shape of the solid or semi-solid support.

[0176] The linking group component can have a variety of structures. Thelinking group component is one which provides suitable spacing for theactivator portion (—CF₂—SO₂—X) to interact freely with molecules orreactive components exposed to the activator portion. The lining groupcomponent is preferably 6-50 atoms long, more preferably 8-40 atomslong, even more preferably 8-30 atoms long, and yet more preferably 8-20atoms long, thus providing sufficient exposure for the attachedactivator portion. Additionally, the linking group component, prior toattachment to the support, will have a attaching portion and a longerchain portion. The attaching portion is that part of the linking groupcomponent which can be directly attached to the solid support. Thisportion can be attached to the solid support via carbon-carbon bondsusing, for example, supports having exposed(poly)trifluorochloroethylene moieties, or preferably, by siloxane bonds(using, for example, glass or silicon oxide as the solid support).Siloxane bonds the support are formed in one embodiment via reactions ofattaching portions bearing trichlorosilyl or trialkoxysilyl groups. Theattaching groups will also have a site for attachment of the longerchain portion. For example, groups which are suitable for attachment toa longer chain portion would include amines, hydroxyl, thiol, andcarboxyl.

[0177] One skilled in the art will recognize that many additionalmethods of attaching linkers to solid and semi-solid supports exist. Onemethod uses an amino resin to which an acid-bearing linker is attachedvia conventional techniques. Another method is the use of aryl etherlinkages by coupling a phenol to a Merrifield (or equivalent) resin.

[0178] The longer chain portion can be any of a variety of moleculeswhich are inert to the subsequent conditions used in the activatorreactions described in further detail below. These longer chain portionscan be ethylene glycol oligomers containing 2-14 monomer units, or morepreferably 2-10 monomer units, and even more preferably 2-8 monomerunits; in addition, the longer chain portions can be diamines, diacids,amino acids, peptides, or combinations thereof. In some embodiments, thelonger chain portion also comprises an activator enhancing portion,i.e., a portion that increases the reactivity of the activator relativeto an alkylene or ethylene glycol linking group. More particularly, anactivator enhancing portion is one that provides additional electronwithdrawing character to the activator portion (e.g., the —CF₂—SO₂—Xportion).

[0179] In one group of embodiments, X is a member selected from thegroup consisting of F and Cl. In another group of embodiments, Lcomprises an activator enhancing portion selected from the groupconsisting of:

[0180] wherein Y is a member selected from the group consisting of achemical bond, O, CO, S, and NR¹; Z is a member selected from the groupconsisting of a chemical bond or CO; each R² is independently a memberselected from the group consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₁-C₈)alkoxy, (C₂-C₈)heteroalkyl, (C₁-C₈)alkylthio, (C₁-C₈)alkylamino,di(C₁-C₈)alkylamino, cyano, nitro and (C₁-C₈)alkylsulfonyl; thesubscript ‘g’ is an integer selected from the group consisting of 0, 1,2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscript ‘i’ is an integer selectedfrom the group consisting of 1, 2, 3, 4, 5, and 6; the subscript ‘j’ isan integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7,8, 9, and 10; the subscript ‘k’ is an integer selected from the groupconsisting of 1, 2, 3, and 4; the subscript ‘m’ is an integer selectedfrom the group consisting of 2 and 3; and the subscript ‘n’ is aninteger selected from the group consisting of 0, 1, 2, 3, and 4. In thegroups described herein as dialkylamino, the alkyl groups can be thesame or different, or can optionally be combined to form a ring havingadditional heteroatoms (e.g., pyrrolidino, morpholino, piperazino).

[0181] In one group of of embodiments, the support-bound activators ofthe present invention are:

[0182] wherein the symbol R¹ and the subscripts g, i, j, k and m allhave the meanings provided above.

[0183] In another group of embodiments, the support-bound activatorshave a formula selected from:

[0184] In each of formulae A and B, X can be F, Cl, trisubstitutedsilyloxy, or OH; Q is O; Z is a chemical bond or C═O; Y is O-support orNR₁-support wherein R₁ is H, (C₁-C₈)alkyl or aryl and the support is aPEG-modified polystyrene or a Merrifield resin; and each R² is asdefined more generally above. The subscripts in formulae A and B are asfollows: ‘g’ is an integer selected from the group consisting of 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, and 11; ‘h’ is an integer selected from thegroup consisting of 1, 2, 3, 4, 5, 6, 7, and 8; ‘i’ is an integerselected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, and 8; ‘j’is an integer selected from the group consisting of 1, 2, 3, and 4; ‘k’is an integer selected from the group consisting of 1, 2, 3, and 4; ‘m’is an integer selected from the group consisting of 2 and 3; ‘n’ is aninteger selected from the group consisting of 0, 1, 2, 3, and 4; and ‘q’is an integer selected from the group consisting of 1, and 2.

[0185] In one particular embodiment in formulae A and B, X is F; Q is O;Z is C═O, Y is NH-support wherein the support is a PEG-modifiedpolystyrene; and each R² is H.

[0186] In still other embodiments, the activated support comprises aplurality of support-bound activators, with a concentration of at least1 nmol support-bound activators per gram of activated support, morepreferably, at least 1 μmol support-bound activators per gram ofactivated support, and even more preferably, at least 1 mmolsupport-bound activators per gram of activated support.

[0187] In another embodiment, the activated support is available in kitform for use in solid phase organic chemistry, as a reagent or catalystin solution phase organic chemistry, as a scavenger resin in solutionphase organic chemistry, as a silylating agent for use in analyticalchemistry, and in particular, in chromatography, and as a reagent forthe production of PET-ready molecules.

[0188] Support-Activated Targets

[0189] In another aspect, the present invention provides asupport-activated target comprising a solid or semi-solid support; anactivating group covalently attached to the solid or semi-solid support,wherein the activating group has the formula:

[0190] wherein L is an linking group component; and a target groupcovalently attached to the solid or semi-solid support; wherein thetarget group can be cleaved from the activating group by a nucleophile.

[0191] Turning first to the solid or semi-solid support, the presentinvention is useful in a variety of solid-phase synthesis applicationsand, accordingly, a variety of supports find utility in this aspect ofthe invention. Typical solid supports include, but are not limited to,cross-linked divinylbenzene-styrene (polystyrene), controlled pore glass(CPG), polyacrylamides, poly(ethyleneglycol)monomethyl ether andpoly(ethylene glycol) (PEG), silica gel, cellulose, acrylic acid graftedpolypropylene, and the like. Additionally, the solid support contains areactive moiety suitable for attaching the linking group component.Suitably reactive moieties include, for example, a carboxylic acid,alcohol, amine, halomethyl and the like which is used to covalentlyattach the linking group component during construction of the presentsupport-bound activators. Many of these supports are available asfunctional polymers having reactive groups. Examples of such supports,include, by way of example, Acryloyl Wang resin, REM resin, Vinylpolystyrene, Vinylsulfonylmethyl polystyrene,(3-Formylindolyl)acetamidomethyl polystyrene,2-(3,5-Dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene,2-(4-Formyl-3-methoxyphenoxy)ethyl polystyrene,4-(4-Formyl-3-methoxyphenoxy)butyryl AM resin, 4-Benzyloxybenzaldehydepolystyrene, Aldehyde Wang resin, Formylpolystyrene, 1% DVB, NovaSyn® TGacetal resin, Polystyrene-CHO, Carboxypolystyrene, NovaSyn® TG carboxyresin, Polystyrene-COOH,4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxy resin,4-Methylbenzhydrylamine resin HCl, 4-Methylbenzhydrylamine resin HCl,9-Fmoc-amino-xanthen-3-yloxy, 9-Fmoc-amino-xanthen-3-yloxy,Amino-(4-methoxyphenyl)methyl polystyrene,Ethylamino-xanthen-3-yloxy-Merrifield resin, NovaSyn® TG Sieber resin,NovaSyn® TGR resin, Rink Amide AM resin, Rink Amide MBHA resin, Rinkamide NovaGel™, Rink amide PEGA resin, Rink Amide resin, Sieber Amideresin, Sieber Ethylamide resin, Amino methyl resin, Amino PEGA resin,Aminomethyl NovaGel™, Aminomethylated polystyrene, N-Methylaminomethylpolystyrene, 4-Fmoc-hydrazinobenzoyl AM resin, 1H-Benzotriazolepolystyrene, Benzotriazole-5-carbamidomethyl polystyrene,N-Fmoc-N-methoxy-β-alanine AM resin, Weinreb AM resin, 4-SulfamylbenzoylAM resin, (±)-1-(2,3-Isopropylidene)glycerol polystyrene,(±)-2,2-Dimethyldioxolan-4-methoxymethyl polystyrene, (±)-1-Glycerolpolystyrene, 4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-Hydroxymethyl-3-methoxyphenoxybutyric acid AM resin,4-Hydroxymethyl-3-methoxyphenoxybutyric acid BHA resin,4-Hydroxymethyl-3-methoxyphenoxybutyric acid MBHA resin,4-Hydroxymethylphenoxyacetyl NovaGel™, 4-Hydroxymethylphenoxyacetyl PEGAresin, HMP resin, HMPA-NovaGel™, HMPB-AM resin, HMPB-BHA resin,HMPB-MBHA resin, Hydroxy-(2-chlorophenyl)methyl polystyrene,Hydroxymethylpolystyrene, NovaSyn® TG HMP resin, p-BenzyloxybenzylAlcohol resin, Polystyrene-CH₂OH, Rink Acid resin, TrichloroacetimidateWang resin, Wang resin, 4-Hydroxymethylbenzoic acid AM resin,4-Hydroxymethylbenzoic acid NovaGel™, 4-Hydroxymethylbenzoic acid PEGAresin, 4-Hydroxyphenylsulfanylmethyl polystyrene,9-(Hydroxymethyl)fluorene-4-carboxamidomethyl polystyrene, HESMpolystyrene, HMBA-AM resin, HMBA-NovaGel™, HMBA-PEGA resin,Hydroxyethylsulfanylmethyl polystyrene, NovaSyn® TG HMBA resin, NovaSyn®TG hydroxy resin, Oxime resin, Aminoethyl photolinker resin,Hydroxyethyl photolinker resins, Hydroxymethyl photolinker resins,3-[4-(Tritylmercapto)phenyl]propionyl AM resin, Mercaptomethylpolystyrene, NovaSyn® TG tritylthiol resin, Thiol 2-chlorotrityl resin,Thiol 4-methoxytrityl resin, (4-Bromophenyl)diisopropylsilyloxymethylpolystyrene, (4-Formylphenyl)diisopropylsilyloxymethyl polystyrene,4-Trityloxyphenyl)diisopropylsilyloxymethyl polystyrene. Solid supportsalso include TENTAGEL™, HYPOGEL™, JANDAJEL™, AND ARGOGEL™. Other solidsupports include PEGylated polystyrene (polystyrene derivatized withpolyethylene glycol), Tentagel-NH₂ resin, and derivatized Tentagel-NH₂resin (e.g., by treatment with acetyl chloride followed by reductionwith LiAlH₄ to provide Tentagel-NHEt resin). See also the NovabiochemCatalogue 2000 for additional resins and immobilized functional groups.

[0192] Such supports may take any size, shape or form, includingparticulate and non-particulate forms or shapes, spheres, disks,pellets, sheets, plugs, pins, crowns, lanterns, in beaded and non-beadedforms, resins, gels, microspheres, as well as amorphous forms andshapes. Embodiments of particulate supports, include beads, pellets,disks, amorphous particles, or other conventional forms. The solid orsemi-solid supports may be used as single particle, as groups ofparticles, as free flowing particles, and may be packed into columns,tubes or other flow-through devices. In a one embodiment, the diameterof the particulate support is 20-2000 micron, preferably 75-500 micron,more preferably 100-200 micron. As one skilled in the art will readilyrecognize, the scope of the present invention is not limited to thesize, form, or shape of the solid or semi-solid support.

[0193] The linking group component can have a variety of structures. Theliking group component is one which provides suitable spacing for thetarget group to interact freely with molecules or reactive componentsexposed to the target group. The liking group component is preferably6-50 atoms long, more preferably 8-40 atoms long, even more preferably8-30 atoms long, and yet more preferably 8-20 atoms long, thus providingsufficient exposure for the attached target group. Additionally, thelinking group component, prior to attachment to the support, will have aattaching portion and a longer chain portion. The attaching portion isthat part of the linking group component which can be directly attachedto the solid support. This portion can be attached to the solid supportvia carbon-carbon bonds using, for example, supports having exposed(poly)trifluorochloroethylene moieties, or preferably, by siloxane bonds(using, for example, glass or silicon oxide as the solid support).Siloxane bonds the support are formed in one embodiment via reactions ofattaching portions bearing trichlorosilyl or trialkoxysilyl groups. Theattaching groups will also have a site for attachment of the longerchain portion. For example, groups which are suitable for attachment toa longer chain portion would include amines, hydroxyl, thiol, andcarboxyl.

[0194] One skilled in the art will recognize that many additionalmethods of attaching linkers to solid and semi-solid supports exist. Onemethod uses an amino resin to which an acid-bearing linker is attachedvia conventional techniques. Another method is the use of aryl etherlinkages by coupling a phenol to a Merrifield (or equivalent) resin.

[0195] The longer chain portion can be any of a variety of moleculeswhich are inert to the subsequent conditions described in further detailbelow. These longer chain portions can be ethylene glycol oligomerscontaining 2-14 monomer units, or more preferably 2-10 monomer units,and even more preferably 2-8 monomer units; in addition, the longerchain portions can be diamines, diacids, amino acids, peptides, orcombinations thereof. In some embodiments, the longer chain portion alsocomprises an activator enhancing portion, i.e., a portion that increasesthe reactivity of the target group relative to an alkylene or ethyleneglycol linking group. More particularly, an activator enhancing portionis one that provides additional electron withdrawing character to thetarget group.

[0196] In another group of embodiments, L comprises an activatorenhancing portion selected from the group consisting of:

[0197] wherein Y is a member selected from the group consisting of achemical bond, O, CO, S, and NR¹; Z is a member selected from the groupconsisting of a chemical bond or CO; each R² is independently a memberselected from the group consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₁-C₈)alkoxy, (C₂-C₈)heteroalkyl, (C₁-C₈)alkylthio, (C₁-C₈)alkylamino,di(C₁-C₈)alkylamino, cyano, nitro and (C₁-C₈)alkylsulfonyl; thesubscript ‘g’ is an integer selected from the group consisting of 0, 1,2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscript ‘i’ is an integer selectedfrom the group consisting of 1, 2, 3, 4, 5, and 6; the subscript ‘j’ isan integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7,8, 9, and 10; the subscript ‘k’ is an integer selected from the groupconsisting of 1, 2, 3, and 4; the subscript ‘m’ is an integer selectedfrom the group consisting of 2 and 3; and the subscript ‘n’ is aninteger selected from the group consisting of 0, 1, 2, 3, and 4. In thegroups described herein as dialkylamino, the alkyl groups can be thesame or different, or can optionally be combined to form a ring havingadditional heteroatoms (e.g., pyrrolidino, morpholino, piperazino).

[0198] In still other embodiments, each solid or semi-solid supportcomprises a plurality of target groups, with a density of at least 1nmol target groups per gram of solid or semi-solid support, morepreferably, at least 1 μmol target groups per gram of solid orsemi-solid support, and even more preferably, at least 1 mmol targetgroups per gram of solid or semi-solid support.

[0199] In other embodiments, the support-activated target can be cleavedfrom the solid or semi-solid support by a reagent. In one group ofembodiments, the reagent comprises a nucleophile; the cleavage step mayalso be promoted by a transition metal catalyst. Once cleaved from thesupport, the resulting compound can be isolated and characterized bymethods standard to the synthesis of organic compounds. As one skilledin the art will readily recognize, the present invention is not limitedby the particular use of the resulting compound.

[0200] Libraries of Support-Activated Targets

[0201] In another aspect, the present invention provides a library ofsupport-activated targets comprising a plurality of support-activatedtarget members, wherein each support-activated target member furthercomprises a solid or semi-solid support; an activating group covalentlyattached to the solid or semi-solid support, wherein the activatinggroup has the formula:

[0202] wherein L is an linking group component; and a target groupcovalently attached to the activating group; wherein the target group ofat least one support-activated target member in the library is differentfrom the target group of at least one other support-activated targetmember in the library.

[0203] The description of the support-activated targets presented aboveis incorporated into this aspect of the present invention. As oneskilled in the art will readily recognize, the present invention is notlimited by the number of different support-activated target members inthe library. Each support-activated target member of the library can becleaved from its solid or semi-solid support by a reagent. In one set ofembodiments the reagent comprises a nucleophile; the cleavage step mayalso be promoted by a transition metal catalyst. The support-activatedtargets and the resulting compounds can be used for a variety ofpurposes, including assays, screens, analysis, and testing. As oneskilled in the art will readily recognize, the present invention is notlimited by the particular use of the resulting compounds.

[0204] Linker Reagents

[0205] In view of the above, the present invention further provideslinker reagents having the formula:

[0206] wherein L is a liking group component; and A is an attachinggroup.

[0207] In one embodiment, the attaching group is a member selected fromthe group consisting of NH₂, NHR, CO₂H, CO₂R, C(O)Cl, OH, SH, andprotected forms thereof, wherein each R is a member independentlyselected from the group consisting of substituted (C₁-C₈)alkyl,unsubstituted (C₁-C₈)alkyl, substituted aryl, and unsubstituted aryl. Inone embodiment, A is NH₂ or CH₂-halogen.

[0208] In further embodiments, L is selected from:

[0209] wherein Y is a member selected from the group consisting of achemical bond, O, CO, S, NR¹; Z is a member selected from the groupconsisting of a chemical bond or CO; each R² is independently a memberselected from the group consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₁-C₈)alkoxy, (C₂-C₈)heteroalkyl, (C₁-C₈)alkylthio, (C₁-C₈)alkylamino,di(C₁-C₈)alkylamino, cyano, nitro and (C₁-C₈)alkylsulfonyl; thesubscript ‘g’ is an integer selected from the group consisting of 0, 1,2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscript ‘i’ is an integer selectedfrom the group consisting of 1, 2, 3, 4, 5, and 6; the subscript ‘j’ isan integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7,8, 9, and 10; the subscript ‘k’ is an integer selected from the groupconsisting of 1, 2, 3, and 4; the subscript ‘m’ is an integer selectedfrom the group consisting of 2 and 3; and the subscript ‘n’ is aninteger selected from the group consisting of 0, 1, 2, 3, and 4. In thegroups described herein as dialkylamino, the alkyl groups can be thesame or different, or can optionally be combined to form a ring havingadditional heteroatoms (e.g., pyrrolidino, morpholino, piperazino).

[0210] In one group of embodiments, the linker reagent has the formula:

HO₂C—(CH₂)_(j)—(CF₂CF₂)_(k)O—(CF₂)₂—SO₂F

[0211] wherein the subscript j is an integer selected from the groupconsisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9. and 10; and the subscript kis an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7,and 8. In one particular embodiment, the subscript j is 1 and thesubscript k is 1.

[0212] In other embodiments, the linker reagent has the formula:

HO₂C—(CH₂)_(g)—(CF₂)_(l)—SO₂F

[0213] wherein the subscript g is an integer selected from the groupconsisting of 3, 4, 5, and 6; and the subscript i is an integer selectedfrom the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

[0214] In other embodiments, the linker reagent has the formula:

[0215] Other embodiments are those represented by formulae C and D:

[0216] in which X is F, Cl, trisubstituted silyloxy or OH; Q is O; A isC(O)Cl, CO₂H or OH; and each R² is as defined above. The subscripts forformulae C and D are as follows: the subscript ‘g’ is an integerselected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,and 11; the subscript ‘h’ is an integer selected from the groupconsisting of 1, 2, 3, 4, 5, 6, 7, and 8; the subscript ‘i’ is aninteger selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7,and 8; the subscript ‘j’ is an integer selected from the groupconsisting of 1, 2, 3, and 4; the subscript ‘n’ is an integer selectedfrom the group consisting of 0, 1, 2, 3, and 4; and the subscript ‘q’ isan integer selected from the group consisting of 0, and 1. In oneembodiment, X is F; Q is O; A is COOH and each R² is H.

[0217] Preparation of Linker Reagents and Support-Bound Activators

[0218] The polymer-supported perfluorosulfonyl fluoride linker of thepresent invention can be prepared as outlined in FIG. 1.

FIG. 1

[0219] FIG. 1 illustrates the preparation of a linker FIG. 1, Structure3 and a support-bound activator FIG. 1, Structure 4 from commerciallyavailable sulfonyl fluoride FIG. 1, Structure 1 (Aldrich Chemical Co.,Milwaukee, Wis., U.S.A.). Thus, treatment of iodide FIG. 1, Structure 1with ethyl vinyl ether in the presence of sodium thiosulfate providesthe aldehyde FIG. 1, Structure 2. Oxidation of the aldehyde provides thecarboxylic acid FIG. 1, Structure 3 which is suitable for attaching to asolid or semi-solid support via an amide- or ester-forming reaction witha suitable nucleophile on the support (e.g., an amino or hydroxy group).Alternatively, the carboxylic acid FIG. 1, Structure 3, can be convertedto its acid chloride using, for example, oxalyl chloride and thenreacted with a suitable amine resin (e.g., Tentagel-NH₂ orTentagel-NHEt). In still other embodiments, the aldehyde FIG. 1,Structure 2 can be attached to a resin via a reductive aminationreaction of an amine resin, aldehyde FIG. 1, Structure 2 and a suitablereducing agent such as sodium borohydride.

[0220] FIG. 2 illustrates the preparation of another linker reagentstarting with 4-chloromethyl benzoyl chloride (Aldrich Chemical Co.,Milwaukee, Wis., U.S.A.).

FIG. 2

[0221] Thus, treatment of 4-chloromethyl benzoyl chloride with t-butanoland triethylamine provides the ester FIG. 2, Structure 5 which can beconverted to the thiol FIG. 2, Structure 6 upon treatment with thiourea,followed by hydrolysis with aqueous KOH. Oxidation of the thiol FIG. 2,Structure 6 with chlorine provides the sulfonyl chloride FIG. 2,Structure 7. Conversion of the sulfonyl chloride to the sulfonate esterFIG. 2, Structure 8 can be accomplished with neopentyl alcohol in thepresence of base (e.g., Et₃N). The sulfonate ester can then be activatedby the stepwise exchange of the a hydrogen atoms with fluorine atoms(tBuLi and NFSi) to give the ester FIG. 2, Structure 9. Deprotection ofthe carboxylic ester with 20% TFA in methylene chloride provides thelinker reagent FIG. 2, Structure 10. The remaining steps in FIG. 2illustrate the attachment of the linker reagent to a support and theconversion to a sulfonic acid FIG. 2, Structure 12.

[0222] Methods of Using the Support-Bound Activators

[0223] In yet another aspect, the present invention provides a methodfor covalently attaching a nucleophile to a compound having a hydroxygroup or an enolizable ketone, the method comprising,

[0224] (a) contacting a compound having a hydroxy group or an enolizableketone with a support-bound activator, wherein said contacting acompound having a hydroxy group or an enolizable ketone with a supportbound activator forms an activated complex; and

[0225] (b) contacting the activated complex with a reagent comprising anucleophile under conditions sufficient to covalently attach thenucleophile to the compound.

[0226] In one embodiment, the support-bound activator has the formula:

[0227] wherein L is a linking group component; X is a member selectedfrom the group consisting of F, and Cl; wherein the support-boundactivator is covalently attached to a solid or semi-solid support.

[0228] Turning first to the solid or semi-solid support, the presentinvention is useful in a variety of solid-phase synthesis applicationsand, accordingly, a variety of supports find utility in this aspect ofthe invention. Typical solid supports include, but are not limited to,cross-linked divinylbenzene-styrene (polystyrene), controlled pore glass(CPG), polyacrylamides, poly(ethyleneglycol)monomethyl ether andpoly(ethylene glycol) (PEG), silica gel, cellulose, acrylic acid graftedpolypropylene, and the like. Additionally, the solid support contains areactive moiety suitable for attaching the linking group component.Suitably reactive moieties include, for example, a carboxylic acid,alcohol, amine, halomethyl and the like which is used to covalentlyattach the linking group component during construction of the presentsupport-bound activators. Many of these supports are available asfunctional polymers having reactive groups. Examples of such supports,include, by way of example, Acryloyl Wang resin, REM resin, Vinylpolystyrene, Vinylsulfonylmethyl polystyrene,(3-Formylindolyl)acetamidomethyl polystyrene,2-(3,5-Dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene,2-(4-Formyl-3-methoxyphenoxy)ethyl polystyrene,4-(4-Formyl-3-methoxyphenoxy)butyryl AM resin, 4-Benzyloxybenzaldehydepolystyrene, Aldehyde Wang resin, Formylpolystyrene, 1% DVB, NovaSyn® TGacetal resin, Polystyrene-CHO, Carboxypolystyrene, NovaSyn® TG carboxyresin, Polystyrene-COOH,4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxy resin,4-Methylbenzhydrylamine resin HCl, 4-Methylbenzhydrylamine resin HCl,9-Fmoc-amino-xanthen-3-yloxy, 9-Fmoc-amino-xanthen-3-yloxy,Amino-(4-methoxyphenyl)methyl polystyrene,Ethylamino-xanthen-3-yloxy-Merrifield resin, NovaSyn® TG Sieber resin,NovaSyn® TGR resin, Rink Amide AM resin, Rink Amide MBHA resin, Rinkamide NovaGel™, Rink amide PEGA resin, Rink Amide resin, Sieber Amideresin, Sieber Ethylamide resin, Amino methyl resin, Amino PEGA resin,Aminomethyl NovaGel™, Aminomethylated polystyrene, N-Methylaminomethylpolystyrene, 4-Fmoc-hydrazinobenzoyl AM resin, 1H-Benzotriazolepolystyrene, Benzotriazole-5-carbamidomethyl polystyrene,N-Fmoc-N-methoxy-β-alanine AM resin, Weinreb AM resin, 4-SulfamylbenzoylAM resin, (±)-1-(2,3-Isopropylidene)glycerol polystyrene,(±)-2,2-Dimethyldioxolan-4-methoxymethyl polystyrene, (±)-1-Glycerolpolystyrene, 4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-(2′,4′-Dimethoxyphenylhydroxymethyl)-phenoxy resin,4-Hydroxymethyl-3-methoxyphenoxybutyric acid AM resin,4-Hydroxymethyl-3-methoxyphenoxybutyric acid BHA resin,4-Hydroxymethyl-3methoxyphenoxybutyric acid MBHA resin,4-Hydroxymethylphenoxyacetyl NovaGel™, 4-Hydroxymethylphenoxyacetyl PEGAresin, HMP resin, HMPA-NovaGel™, HMPB-AM resin, HMPB-BHA resin,HMPB-MBHA resin, Hydroxy-(2-chlorophenyl)methyl polystyrene,Hydroxymethylpolystyrene, NovaSyn® TG HMP resin, p-BenzyloxybenzylAlcohol resin, Polystyrene-CH₂OH, Rink Acid resin, TrichloroacetimidateWang resin, Wang resin, 4-Hydroxymethylbenzoic acid AM resin,4-Hydroxymethylbenzoic acid NovaGel™, 4-Hydroxymethylbenzoic acid PEGAresin, 4-Hydroxyphenylsulfanylmethyl polystyrene,9-(Hydroxymethyl)fluorene-4-carboxamidomethyl polystyrene, HESMpolystyrene, HMBA-AM resin, HMBA-NovaGel™, HMBA-PEGA resin,Hydroxyethylsulfanylmethyl polystyrene, NovaSyn® TG HMBA resin, NovaSyn®TG hydroxy resin, Oxime resin, Aminoethyl photolinker resin,Hydroxyethyl photolinker resins, Hydroxymethyl photolinker resins,3-[4-(Tritylmercapto)phenyl]propionyl AM resin, Mercaptomethylpolystyrene, NovaSyn® TG tritylthiol resin, Thiol 2-chlorotrityl resin,Thiol 4-methoxytrityl resin, (4-Bromophenyl)diisopropylsilyloxymethylpolystyrene, (4-Formylphenyl)diisopropylsilyloxymethyl polystyrene,(4-Trityloxyphenyl)diisopropylsilyloxymethyl polystyrene. Solid supportsalso include TENTAGEL™, HYPOGEL™, JANDAJEL™, AND ARGOGEL™. Other solidsupports include PEGylated polystyrene (polystyrene derivatized withpolyethylene glycol), Tentagel-NH₂ resin, and derivatized Tentagel-NH₂resin (e.g., by treatment with acetyl chloride followed by reductionwith LiAlH₄ to provide Tentagel-NHEt resin). See also the NovabiochemCatalogue 2000 for additional resins and immobilized functional groups.

[0229] Such supports may take any size, shape or form, includingparticulate and non-particulate forms or shapes, spheres, disks,pellets, sheets, plugs, pins, crowns, lanterns, in beaded and non-beadedforms, resins, gels, microspheres, as well as amorphous forms andshapes. Embodiments of particulate supports, include beads, pellets,disks, amorphous particles, or other conventional forms. The solid orsemi-solid supports may be used as single particle, as groups ofparticles, as free flowing particles, and may be packed into columns,tubes or other flow-through devices. In a one embodiment, the diameterof the particulate support is 20-2000 micron, preferably 75-500 micron,more preferably 100-200 micron. As one skilled in the art will readilyrecognize, the scope of the present invention is not limited to thesize, form, or shape of the solid or semi-solid support.

[0230] The linking group component can have a variety of structures. Thelinking group component is one which provides suitable spacing for theactivator portion (—CF₂—SO₂—X) to interact freely with molecules orreactive components exposed to the activator portion. The linking groupcomponent is preferably 6-50 atoms long, more preferably 8-40 atomslong, even more preferably 8-30 atoms long, and yet more preferably 8-20atoms long, thus providing sufficient exposure for the attachedactivator portion. Additionally, the linking group component, prior toattachment to the support, will have a attaching portion and a longerchain portion. The attaching portion is that part of the linking groupcomponent which can be directly attached to the solid support. Thisportion can be attached to the solid support via carbon-carbon bondsusing, for example, supports having exposed(poly)trifluorochloroethylene moieties, or preferably, by siloxane bonds(using, for example, glass or silicon oxide as the solid support).Siloxane bonds the support are formed in one embodiment via reactions ofattaching portions bearing trichlorsilyl or trialkoxysilyl groups. Theattaching groups will also have a site for attachment of the longerchain portion. For example, groups which are suitable for attachment toa longer chain portion would include amines, hydroxyl, thiol, andcarboxyl.

[0231] One skilled in the art will recognize that many additionalmethods of attaching linkers to solid and semi-solid supports exist. Onemethod uses an amino resin to which an acid-bearing linker is attachedvia conventional techniques. Another method is the use of aryl etherlinkages by coupling a phenol to a Merrifield (or equivalent) resin.

[0232] The longer chain portion can be any of a variety of moleculeswhich are inert to the subsequent conditions used in the activatorreactions described in further detail below. These longer chain portionscan be ethylene glycol oligomers containing 2-14 monomer units, or morepreferably 2-10 monomer units, and even more preferably 2-8 monomerunits; in addition, the longer chain portions can be diamines, diacids,amino acids, peptides, or combinations thereof. In some embodiments, thelonger chain portion also comprises an activator enhancing portion,i.e., a portion that increases the reactivity of the activator relativeto an alkylene or ethylene glycol liking group. More particularly, anactivator enhancing portion is one that provides additional electronwithdrawing character to the activator portion (e.g., the —CF₂—SO₂—Xportion).

[0233] In one group of embodiments, X is a member selected from thegroup consisting of F and Cl. In another group of embodiments, Lcomprises an activator enhancing portion selected from the groupconsisting of:

[0234] wherein Y is a member selected from the group consisting of achemical bond, O, CO, S, and NR¹; Z is a member selected from the groupconsisting of a chemical bond or CO; each R² is independently a memberselected from the group consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₁-C₈)alkoxy, (C₂-C₈)heteroalkyl, (C₁-C₈)alkylthio, (C₁-C₈)alkylamino,di(C₁-C₈)alkylamino, cyano, nitro and (C₁-C₈)alkylsulfonyl; thesubscript ‘g’ is an integer selected from the group consisting of 0, 1,2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscript ‘i’ is an integer selectedfrom-the group consisting of 1, 2, 3, 4, 5, and 6; the subscript ‘j’ isan integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7,8, 9, and 10; the subscript ‘k’ is an integer selected from the groupconsisting of 1, 2, 3, and 4; the subscript ‘m’ is an integer selectedfrom the group consisting of 2 and 3; and the subscript ‘n’ is aninteger selected from the group consisting of 0, 1, 2, 3, and 4. In thegroups described herein as dialkylamino, the alkyl groups can be thesame or different, or can optionally be combined to form a ring havingadditional heteroatoms (e.g., pyrrolidino, morpholino, piperazino).

[0235] In another embodiment, the support-bound activator is availablein kit form for use in solid phase organic chemistry, as a reagent orcatalyst in solution phase organic chemistry, as a scavenger resin insolution phase organic chemistry, as a silylating agent for use inanalytical chemistry, and in particular, in chromatography, and as areagent for the production of PET-ready molecules.

[0236] In one group of of embodiments, the support-bound activators ofthe present invention are:

[0237] wherein the symbol R¹ and the subscripts g, i, j, k and m allhave the meanings provided above.

[0238] In another group of embodiments, the support-bound activatorshave a formula selected from:

[0239] In each of formulae A and B, X can be F and Cl; Q is O; Z is achemical bond or C═O; Y is O-support or NR₁-support wherein R₁ is H,(C₁-C₈)alkyl or aryl and the support is a PEG-modified polystyrene or aMerrifield resin; and each R² is as defined more generally above. Thesubscripts in formulae A and B are as follows: ‘g’ is an integerselected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,and 11; ‘h’ is an integer selected from the group consisting of 1, 2, 3,4, 5, 6, 7, and 8; ‘i’ is an integer selected from the group consistingof 0, 1, 2, 3, 4, 5, 6, 7, and 8; ‘j’ is an integer selected from thegroup consisting of 1, 2, 3, and 4; ‘k’ is an integer selected from thegroup consisting of 1, 2, 3, and 4; ‘m’ is an integer selected from thegroup consisting of 2 and 3; ‘n’ is an integer selected from the groupconsisting of 0, 1, 2, 3, and 4; and ‘q’ is an integer selected from thegroup consisting of 1, and 2.

[0240] In one particular embodiment in formulae A and B, X is F; Q is O;Z is C═O, Y is NH-support wherein the support is a PEG-modifiedpolystyrene; and each R² is H.

[0241] In one group of embodiments, the reagent is a member selectedfrom the group consisting of an organostannane compound, an organozinccompound, an organoboron compound, an organolithium compound, anorganoaluminum compound, a Grignard reagent, an organosilicon compound,an organocopper compound, a thiol, a dialkylphosphite, an amine, a metalhalide, and a halogen.

[0242] In one group of embodiments, the nucleophile is a member selectedfrom the group consisting of an amine, a halogen anion, an aryl moiety,an alkyl moiety, a cyano, and a hydride. In preferred embodiments, atransition metal catalyst is used in conjunction with the nucleophilicreagent.

[0243] In still other embodiments, the activated complex is treatedunder the appropriate conditions to afford a radioisotopically labeledcompound without significant contamination from undesired compounds.This particular embodiment is expected to find significant utility inthe field of medicinal chemistry, in which the use of imaging agentsremains an important technique to non-invasively evaluate human andanimal conditions. One newly emerging field is that of positron emissiontomography (PET). Briefly, this involves the use of short livedradioisotopes incorporated into known or potential drug substances andevaluation of their relative distribution throughout the body. Onesignificant drawback to existing methods is the preparation of theintended labeled compound and their use before the radioisotopes hasdecayed below that of useful intensity. One must prepare, purify, anduse the intended labeled compound within a few hours in a PET study.Merely by way of example, U.S. Pat. No. 6,307,372, entitled “Methods forhigh throughput chemical screening using magnetic resonance imaging” isherein incorporated by reference in its entirety. Thus, there is a needin the art for a method for rapidly preparing and purifying PET-readymolecules. An approach that would satisfy this need would be to providesupport-bound targets that can be released from the support uponreaction with radioisotopically labeled nucleophiles.

[0244] For example, treatment of a support-bound aryl perfluorosulfonatespecies with ¹¹C methyl lithium promotes a cleavage/derivatizationcascade which results in the release of a ¹¹C methyl-substituted arylspecies suitable for use in a PET experiment. Another example isincorporation of ¹⁸F into aryl species to afford arylfluorides, commonlyfound in drug substances.

[0245] In one embodiment, the nucleophile is an ¹⁸F anion. The labeledcompounds resulting from the reaction of the ¹⁸F anion with theactivated complex can be used as PET-ready molecules for medical imagingpurposes.

[0246] In still another embodiment, the nucleophile is a ¹¹CH₃ anion.Examples of reagents for providing the ¹¹CH₃ anion are ¹¹Cmethyl-lithium or ¹¹C methyl-cuprate. The labeled compounds resultingfrom the reaction of the ¹¹CH₃ anion with the activated complex can beused as PET-ready molecules for medical imaging purposes.

[0247] In yet another embodiment, the present invention provides amethod for transformation or substitution of a hydroxy group in acompound having a hydroxy group or an enolizable carbonyl group, themethod comprising,

[0248] (a) contacting the compound having a hydroxy group or anenolizable carbonyl group with a support-bound activator having theformula:

[0249] wherein L is a linking group component; X is selected from F, andCl; and the support bound activator is covalently attached to a solid orsemi-solid support, under conditions sufficient to form an activatedcomplex having the formula:

[0250] wherein -X is now —OQ and Q represents said compound; O is theoxygen atom vestige of the hydroxy group or enolizable ketone present insaid compound; and L is the linking group component; and

[0251] (b) contacting the activated complex with a reagent comprising anucleophile to transform or substitute said hydroxy group and form a newcompound having the formula:

R^(x)-Q.

[0252] A variety of transformations can be accomplished using themethods herein. More particularly, the transformations includedeoxygenations, cross-couplings (e.g., via organometallic reagents usedin Suzuki, Stille, Heck, and organozinc coupling reactions), COinsertion, cyanide displacements, and numerous other reactions known tobe suitable with vinyl or aryl triflates (see, Ritter, Synthesis8:735-762 (1993)).

[0253] In one group of embodiments, the hydroxy group is present on anaromatic ring system such as a substituted or unsubstituted benzene orheteroaryl ring and the reagent is a hydride source which results in thereductive cleavage of the compound Q.

[0254] In one particular group of embodiments, the support-boundactivator is a polymer-supported perfluorosulfonate linker as shown inFIG. 3. Deoxygenation of a polymer-supported aryl perfluorosulfonate canbe carried out by a palladium-mediated reduction. The polymer-bound arylperfluorosulfonates can be efficiently cleaved with Et₃N/HCO₂H in thepresence of a catalytic amount of Pd(OAc)₂ and1,3-bis(diphenylphosphino)propane (dppp) in high yields to produce thereduced arenes under mild conditions. Table 1 provides examples ofcompounds (Q-OH) that can be reduced (Q-H) using the methods of theinvention.

TABLE 1 ArOH ArH Yield of ArH 14a

81 14b

76 14c

88 14d

90 14e

86 14f

85 14g

88 14h

75 14i

63 14j

14k

86 14l

80

[0255] In another particular group of embodiments, the transformation isa cross-coupling reaction. In this group of embodiments, the activatedcomplex is

[0256] wherein -X is now —Oar and Ar is an aryl or heteroaryl group.

[0257] In one group of embodiments, the reagent is an aryl boronic acid(Ar′B(OH)₂) which provides a coupled compound having the formula Ar—Ar′.FIG. 4 provides an illustration of this embodiment using a nonaflatelinker of the present invention, and Table 2 provides an illustration ofthe compounds and products provided. For simplicity, the linker is notshown in Table 2.

TABLE 2 Resin Aryl boronic acid Product (Ar′—Ar)

[0258] In still other embodiments, the activated complex is subjected toadditional synthetic transformations prior to a cross-coupling (e.g.,Suzuki, Stille, Heck, Sonogashira, Buchwald) which releases the productfrom the resin. FIG. 5 illustrates certain reactions that can be appliedto the activated complex, while Table 3 illustrates various startingmaterials and products that can be obtained using the linkinggroup/activators described herein.

TABLE 3 R¹NH₂ R²COCl Boronic Acid Product

[0259] The perfluorosulfonyl fluoride linker of this invention was usedto a multi-step synthesis of the therapeutic agent, meclizine asoutlined in FIG. 6.

[0260] Strongly Acidic Support

[0261] In another aspect, the present invention provides a stronglyacidic support comprising a solid or semi-solid support; and at leastone support-bound strongly acid group having the formula:

[0262] wherein L is a linking group component; and X is OH; and whereinthe support-bound strongly acid group is covalently attached to thesolid or semi-solid support.

[0263] Turning first to the solid or semi-solid support, the presentinvention is useful in a variety of solid-phase synthesis applicationsand, accordingly, a variety of supports find utility in this aspect ofthe invention. Typical solid supports include, but are not limited to,cross-linked divinylbenzene-styrene (polystyrene), controlled pore glass(CPG), polyacrylamides, poly(ethyleneglycol)monomethyl ether andpoly(ethylene glycol) (PEG), silica gel, cellulose, acrylic acid graftedpolypropylene, and the like. Additionally, the solid support contains areactive moiety suitable for attaching the linking group component.Suitably reactive moieties include, for example, a carboxylic acid,alcohol, amine, halomethyl and the like which is used to covalentlyattach the linking group component during construction of the presentsupport-bound activators. Many of these supports are available asfunctional polymers having reactive groups. Examples of such supports,include, by way of example, Acryloyl Wang resin, REM resin, Vinylpolystyrene, Vinylsulfonylmethyl polystyrene,(3-Formylindolyl)acetamidomethyl polystyrene,2-(3,5-Dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene,2-(4-Formyl-3-methoxyphenoxy)ethyl polystyrene,4-(4-Formyl-3-methoxyphenoxy)butyryl AM resin, 4-Benzyloxybenzaldehydepolystyrene, Aldehyde Wang resin, Formylpolystyrene, 1% DVB, NovaSyn® TGacetal resin, Polystyrene-CHO, Carboxypolystyrene, NovaSyn® TG carboxyresin, Polystyrene-COOH,4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)phenoxy resin,4-Methylbenzhydrylamine resin HCl, 4-Methylbenzhydrylamine resin HCl,9-Fmoc-amino-xanthen-3-yloxy, 9-Fmoc-amino-xanthen-3-yloxy,Amino-(4methoxyphenyl)methyl polystyrene,Ethylamino-xanthen-3-yloxy-Merrifield resin, NovaSyn® TG Sieber resin,NovaSyn® TGR resin, Rink Amide AM resin, Rink Amide MBHA resin, Rinkamide NovaGel™, Rink amide PEGA resin, Rink Amide resin, Sieber Amideresin, Sieber Ethylamide resin, Amino methyl resin, Amino PEGA resin,Aminomethyl NovaGel™, Aminomethylated polystyrene, N-Methylaminomethylpolystyrene, 4-Fmoc-hydrazinobenzoyl AM resin, 1H-Benzotriazolepolystyrene, Benzotriazole-5-carbamidomethyl polystyrene,N-Fmoc-N-methoxy-β-alanine AM resin, Weinreb AM resin, 4-SulfamylbenzoylAM resin, (±)-1-(2,3-Isopropylidene)glycerol polystyrene,(±)-2,2-Dimethyldioxolan-4-methoxymethyl polystyrene, (±)-1-Glycerolpolystyrene, 4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-Hydroxymethyl-3-methoxyphenoxybutyric acid AM resin,4-Hydroxymethyl-3-methoxyphenoxybutyric acid BHA resin,4-Hydroxymethyl-3methoxyphenoxybutyric acid MBHA resin,4-Hydroxymethylphenoxyacetyl NovaGel™, 4-Hydroxymethylphenoxyacetyl PEGAresin, HMP resin, HMPA-NovaGel™, HMPB-AM resin, HMPB-BHA resin,HMPB-MBHA resin, Hydroxy-(2-chlorophenyl)methyl polystyrene,Hydroxymethylpolystyrene, NovaSyn™ TG HMP resin, p-BenzyloxybenzylAlcohol resin, Polystyrene-CH₂OH, Rink Acid resin, TrichloroacetimidateWang resin, Wang resin, 4-Hydroxymethylbenzoic acid AM resin,4-Hydroxymethylbenzoic acid NovaGel™, 4-Hydroxymethylbenzoic acid PEGAresin, 4-Hydroxyphenylsulfanylmethyl polystyrene,9-(Hydroxymethyl)fluorene-4-carboxamidomethyl polystyrene, HESMpolystyrene, HMBA-AM resin, HMBA-NovaGel™, HBA-PEGA resin,Hydroxyethylsulfanylmethyl polystyrene, NovaSyn® TG HMBA resin, NovaSyn®TG hydroxy resin, Oxime resin, Aminoethyl photolinker resin,Hydroxyethyl photolinker resins, Hydroxymethyl photolinker resins,3-[4-(Tritylmercapto)phenyl]propionyl AM resin, Mercaptomethylpolystyrene, NovaSyn® TG tritylthiol resin, Thiol 2-chlorotrityl resin,Thiol 4-methoxytrityl resin, (4-Bromophenyl)diisopropylsilyloxymethylpolystyrene, (4-Formylphenyl)diisopropylsilyloxymethyl polystyrene,(4Trityloxyphenyl)diisopropylsilyloxymethyl polystyrene. Solid supportsalso include TENTAGEL™, HYPOGEL™, JANDAJEL™, AND ARGOGEL™. Other solidsupports include PEGylated polystyrene (polystyrene derivatized withpolyethylene glycol), Tentagel-NH₂ resin, and derivatized Tentagel-NH₂resin (e.g., by treatment with acetyl chloride followed by reductionwith LiAlH₄ to provide Tentagel-NHEt resin). See also the NovabiochemCatalogue 2000 for additional resins and immobilized functional groups.

[0264] Such supports may take any size, shape or form, includingparticulate and non-particulate forms or shapes, spheres, disks,pellets, sheets, plugs, pins, crowns, lanterns, in beaded and non-beadedforms, resins, gels, microspheres, as well as amorphous forms andshapes. Embodiments of particulate supports, include beads, pellets,disks, amorphous particles, or other conventional forms. The solid orsemi-solid supports may be used as single particle, as groups ofparticles, as free flowing particles, and may be packed into columns,tubes or other flow-through devices. In a one embodiment, the diameterof the particulate support is 20-2000 micron, preferably 75-500 micron,more preferably 100-200 micron. As one skilled in the art will readilyrecognize, the scope of the present invention is not limited to thesize, form, or shape of the solid or semi-solid support.

[0265] The liking group component can have a variety of structures. Thelinking group component is one which provides suitable spacing for theactivator portion (—CF₂—SO₂—OH) to interact freely with molecules orreactive components exposed to the activator portion. The linking groupcomponent is preferably 6-50 atoms long, more preferably 8-40 atomslong, even more preferably 8-30 atoms long, and yet more preferably 8-20atoms long, thus providing sufficient exposure for the attachedactivator portion. Additionally, the linking group component, prior toattachment to the support, will have a attaching portion and a longerchain portion. The attaching portion is that part of the linking groupcomponent which can be directly attached to the solid support. Thisportion can be attached to the solid support via carbon-carbon bondsusing, for example, supports having exposed(poly)trifluorochloroethylene moieties, or preferably, by siloxane bonds(using, for example, glass or silicon oxide as the solid support).Siloxane bonds the support are formed in one embodiment via reactions ofattaching portions bearing trichlorosilyl or trialkoxysilyl groups. Theattaching groups will also have a site for attachment of the longerchain portion. For example, groups which are suitable for attachment toa longer chain portion would include amines, hydroxyl, thiol, andcarboxyl.

[0266] One skilled in the art will recognize that many additionalmethods of attaching linkers to solid or semi-solid supports exist. Onemethod uses an amino resin to which an acid-bearing linker is attachedvia conventional techniques. Another method is the use of aryl etherlinkages by coupling a phenol to a Merrifield (or equivalent) resin.

[0267] The longer chain portion can be any of a variety of moleculeswhich are inert to the subsequent conditions used in the activatorreactions described in further detail below. These longer chain portionscan be ethylene glycol oligomers containing 2-14 monomer units, or morepreferably 2-10 monomer units, and even more preferably 2-8 monomerunits; in addition, the longer chain portions can be diamines, diacids,amino acids, peptides, or combinations thereof. In some embodiments, thelonger chain portion also comprises an activator enhancing portion,i.e., a portion that increases the reactivity of the activator relativeto an alkylene or ethylene glycol linking group. More particularly, anactivator enhancing portion is one that provides additional electronwithdrawing character to the activator portion (e.g., the —CF₂—SO₂—OHportion).

[0268] In another group of embodiments, L comprises an activatorenhancing portion selected from the group consisting of:

[0269] wherein Y is a member selected from the group consisting of achemical bond, O, CO, S, and NR¹; Z is a member selected from the groupconsisting of a chemical bond or CO; each R² is independently a memberselected from the group-consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₁-C₈)alkoxy, (C₂-C₈)heteroalkyl, (C₁-C₈)alkylthio, (C₁-C₈)alkylamino,di(C₁-C₈)alkylamino, cyano, nitro and (C₁-C₈)alkylsulfonyl; thesubscript ‘g’ is an integer selected from the group consisting of 0, 1,2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscript ‘i’ is an integer selectedfrom the group consisting of 1, 2, 3, 4, 5, and 6; the subscript ‘j’ isan integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7,8, 9, and 10; the subscript ‘k’ is an integer selected from the groupconsisting of 1, 2, 3, and 4; the subscript ‘m’ is an integer selectedfrom the group consisting of 2 and 3; and the subscript ‘n’ is aninteger selected from the group consisting of 0, 1, 2, 3, and 4. In thegroups described herein as dialkylamino, the alkyl groups can be thesame or different, or can optionally be combined to form a ring havingadditional heteroatoms (e.g., pyrrolidino, morpholino, piperazino).

[0270] In another group of embodiments, the support-bound activatorshave a formula selected from:

[0271] In each of formulae A and B, X is OH; Q is O; Z is a chemicalbond or C═O; Y is O-support or NR₁-support wherein R₁ is H, (C₁-C₈)alkylor aryl and the support is a PEG-modified polystyrene or a Merrifieldresin; and each le is as defined more generally above. The subscripts informulae A and B are as follows: ‘g’ is an integer selected from thegroup consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11; ‘h’ is aninteger selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and8; ‘i’ is an integer selected from the group consisting of 0, 1, 2, 3,4, 5, 6, 7, and 8; ‘j’ is an integer selected from the group consistingof 1, 2, 3, and 4; ‘k’ is an integer selected from the group consistingof 1, 2, 3, and 4; ‘m’ is an integer selected from the group consistingof 2 and 3; ‘n’ is an integer selected from the group consisting of 0,1, 2, 3, and 4; and ‘q’ is an integer selected from the group consistingof 1, and 2.

[0272] In one particular embodiment in formulae A and B, X is OH; Q isO; Z is C═O, Y is NH-support wherein the support is a PEG-modifiedpolystyrene; and each R² is H.

[0273] In still other embodiments, each solid or semi-solid supportcomprises a plurality of support-bound strongly acid groups, with adensity of at least 1 μmol support-bound strongly acid groups per gramof solid or semi-solid support, more preferably, at least 1 μmolsupport-bound strongly acid groups per gram of solid or semi-solidsupport, and even more preferably, at least 1 mmol support-boundstrongly acid groups per gram of solid or semi-solid support.

[0274] In another embodiment, the strongly acidic support is availablein kit form for use as a reagent or catalyst in solution phase organicchemistry, or as a scavenger resin in solution phase organic chemistry.

[0275] The preparation of the resin-bound perfluorosulfonic acid FIG. 7,Structure 25 is outlined in FIG. 7, and the synthesis of the resin-boundperfluorosulfonic acid FIG. 2, Structure 12 is outlined FIG. 2.

[0276] The highly acidic supports of this invention provide a solidphase reagent that is chemically analogous to perfluorosulfonic acids;furthermore, in one embodiment of the present invention, the vastmajority of surface-bound perfluorosulfonic acid sites are readilyavailable for reaction, thus allowing the use of this embodiment bothcatalytically and stoichiometrically.

[0277] In addition to being used as highly acidic solid phase catalystsand reagents, support-bound acidic groups can be used as scavengerresins. Such a use has been described in the generation of diversecollections of compounds. Merely by way of example, “Polymer SupportedReagents Handbook” (NovaBiochem, 2001), is incorporated herein byreference. In general, resins capable of capturing excess reagents,products, or unwanted byproducts from reaction mixtures have foundwidespread use in organic chemistry laboratories, and in particular, areconsidered to be highly important in the pharmaceutical arena. Theseresins can be employed in both covalent and ionic fashions.

[0278] For example, an amine can react with an acid chloride to affordan amide as the desired product. The most common method of obtaining theproduct in a high yield is to use one of the two reaction partners inexcess and to then separate the product from excess reagent. When usingan excess of the acid chloride, the reaction mixture can be treated witha primary or secondary amine-containing resin after the reaction tocovalently capture the excess acid chloride as a polymer bound amide.Simple filtration of the resin from the reaction mixture would affordthe desired product amide essentially free of excess acid chloride.Alternatively, when using an excess of the amine component, the reactionmixture can be treated with an acid-containing resin (i.e., a strongcation exchange resin) to ionically capture the excess amine as itsammonium salt form on the resin. Simple filtration of the resin from thereaction mixture would afford the desired amide essentially free of theexcess amine.

[0279] To date there have been no scavenger resins described containingacidic groups stronger than phenylsulfonic acids (e.g., DOWEX™ (DowChemical Company, Midland, Mich.) and related resins). These resins areinherently limited in their ability to capture weakly basic compounds byvirtue of their modest acidity. There exists the need to develop resinsof much higher acidity (i.e. highly acidic supports) which are swellablein a variety of solvents, capable of achieving high loading (i.e.loading of >0.2 mmol/g, preferably >0.5 mmol/g, more preferably >0.8mmol/g), and stable to mechanical forces typical during washing steps.

[0280] Another application of scavenger supports has been termed“capture and release,” a technique in which targets are first captured(i.e., attached to a support) from a chemical reaction solution, then,the unwanted compounds removed by filtration or other similar methods,and finally, the desired compound is released from the support. SeeBhat, J. Comb. Chem. 2000, 2, 597. This final release step can beperformed by a multitude of possible methods depending on the nature ofthe attachment of the targets to the support. When using resins to“capture” molecules to the support as salts, the displacement step maybe conveniently performed by treating the support with a solutioncontaining a volatile amine such as ammonia. Molecules covalentlyattached to the support can be cleaved under a variety of conditions.

[0281] Thus, another embodiment of the polymer-supported compositionsdescribed in this is the use of the polymer-supported compositions aseither covalent or ionic scavenger resins. An embodiment of thisinvention is to capture amines, thiols, alcohols, phenols, ketones andother species capable of forming stable triflate products as theirrespective polymer-supported triflates, and then to filter them awayfrom reaction mixtures. A preferred embodiment of this invention is toexpose a reaction mixture containing amine and other basic compoundscapable of forming ionic triflate salts with the novel compositionsdisclosed herein and to then filter away said basic species. See Example8 below for an illustrative use of the highly acidic supports of thepresent invention as scavenger resins.

[0282] Those skilled in the art will recognize that thepolymer-supported perfluorsulfonic acids described herein aredramatically more acidic than the known cation exchange resins, and assuch, will be capable of effectively scavenging a broader range ofcompounds.

[0283] Silylating Support

[0284] In the field of analytical chemistry, it is common to chemicallyderivatize molecules to make them more suitable for variouschromatographic techniques. The general principles of compoundderivatization for chromatography are described in “Handbook ofDerivatives for Chromatography: by K. Blau and J. Halket (Wiley,England, 1993), which is incorporated herein by reference. For example,treatment of molecules containing hydroxyl or acid groups with any oneof a number of silylating agents renders silyl ethers or esters that aremore volatile than the parent compound, and thus more amenable toanalysis via gas chromatography. It is also common to derivatizecompounds to alter their properties in BPLC applications. One drawbackin current methods for compound derivatization is the necessity toseparate excess derivatization reagents from the desired, derivatizedproduct. In addition, highly reactive derivatization regents, such aschlorotrimethylsilane and other silylating reagents, have been observedto both deactivate chromatography columns and contaminate flameionization detectors in gas chromatographs with SiO2 rendering themineffective. A technique of employing highly reactive, polymer-supportedderivatization reagents would be very important and find widespread usethrough the industry.

[0285] One aspect of the present invention provides for a silylatingsupport, and in particular, silylating polymer-supported reagents, thatafford the desired derivatized products free of contaminating reagents.Whereas silyltriflates are widely known as extremely reactive silylatingreagents in solution, the corresponding polymer-supported silyltriflateshave not been widely employed. NAFION™-TMS has been made by Noyori,Tetrahedron Lett. 1980, 21, 767 by heating the acid form of the polymerwith chlorotrimethylsilane and sulfuric acid. Furthermore, thepolymer-supported silyl triflates that have been described in theliterature (e.g., Smith, Tetrahedron Lett. 1999, 40, 3285 and Porco,Tetrahedron Lett. 1999, 40, 3289) are trifylating resins and notsilylating resins. Thus, there is a need in the art for highly-reactive,silylating resins that are swellable and wettable by organic solvents,and which can thus readily act as stoichiometric silylating reagents.The silylating support of the present invention fulfills this need.

[0286] In another aspect, the present invention provides a silylatingsupport comprising a solid or semi-solid support; and at least onesupport-bound silylating group having the formula:

[0287] wherein L is a linking group component; X is a trisubstitutedsilyloxy; wherein the support-bound silylating group is covalentlyattached to the solid or semi-solid support.

[0288] Turning first to the solid or semi-solid support, the presentinvention is useful in a variety of solid-phase synthesis applicationsand, accordingly, a variety of supports find utility in this aspect ofthe invention. Typical solid supports include, but are not limited to,cross-linked divinylbenzene-styrene (polystyrene), controlled pore glass(CPG), polyacrylamides, poly(ethyleneglycol)monomethyl ether andpoly(ethylene glycol) (PEG), silica gel, cellulose, acrylic acid graftedpolypropylene, and the like. Additionally, the solid support contains areactive moiety suitable for attaching the linking group component.Suitably reactive moieties include, for example, a carboxylic acid,alcohol, amine, halomethyl and the like which is used to covalentlyattach the linking group component during construction of the presentsupport-bound activators. Many of these supports are available asfunctional polymers having reactive groups. Examples of such supports,include, by way of example, Acryloyl Wang resin, REM resin, Vinylpolystyrene, Vinylsulfonylmethyl polystyrene,(3-Formylindolyl)acetamidomethyl polystyrene,2-(3,5-Dimethoxy-4-formylphenoxy)ethoxymethyl polystyrene,2-(4-Formyl-3-methoxyphenoxy)ethyl polystyrene,4-(4-Formyl-3-methoxyphenoxy)butyryl AM resin, 4-Benzyloxybenzaldehydepolystyrene, Aldehyde Wang resin, Formylpolystyrene, 1% DVB, NovaSyn® TGacetal resin, Polystyrene-CHO, Carboxypolystyrene, NovaSyn® TG carboxyresin, Polystyrene-COOH,4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)phenoxy resin,4-Methylbenzhydrylamine resin HCl, 4-Methylbenzhydrylamine resin HCl,9-Fmoc-amino-xanthen-3-yloxy, 9-Fmoc-amino-xanthen-3-yloxy,Amino-(4methoxyphenyl)methyl polystyrene,Ethylamino-xanthen-3-yloxy-Merrifield resin, NovaSyn® TG Sieber resin,NovaSyn® TGR resin, Rink Amide AM resin, Rink Amide MBHA resin, Rinkamide NovaGel™, Rink amide PEGA resin, Rink Amide resin, Sieber Amideresin, Sieber Ethylamide resin, Amino methyl resin, Amino PEGA resin,Aminomethyl NovaGel™, Aminomethylated polystyrene, N-Methylaminomethylpolystyrene, 4-Fmoc-hydrazinobenzoyl AM resin, 1H-Benzotriazolepolystyrene, Benzotriazole-5-carbamidomethyl polystyrene,N-Fmoc-N-methoxy-β-alanine AM resin, Weinreb AM resin, 4-SulfamylbenzoylAM resin, (±)-1-(2,3-Isopropylidene)glycerol polystyrene,(±)-2,2-Dimethyldioxolan-4-methoxymethyl polystyrene, (±)-1-Glycerolpolystyrene, 4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-(2′,4′-Dimethoxyphenyl-hydroxymethyl)-phenoxy resin,4-Hydroxymethyl-3-methoxyphenoxybutyric acid AM resin,4-Hydroxymethyl-3-methoxyphenoxybutyric acid BHA resin,4-Hydroxymethyl-3methoxyphenoxybutyric acid MBHA resin,4-Hydroxymethylphenoxyacetyl NovaGel™, 4-Hydroxymethylphenoxyacetyl PEGAresin, HMP resin, HMPA-NovaGel™, HWPBAM resin, HMPB-BHA resin, HMPB-MBHAresin, Hydroxy-(2-chlorophenyl)methyl polystyrene,Hydroxymethylpolystyrene, NovaSyn® TG HMP resin, p-BenzyloxybenzylAlcohol resin, Polystyrene-CH₂OH. Rink Acid resin, TrichloroacetimidateWang resin, Wang resin, 4-Hydroxymethylbenzoic acid AM resin,4-Hydroxymethylbenzoic acid NovaGel™, 4-Hydroxymethylbenzoic acid PEGAresin, 4-Hydroxyphenylsulfanylmethyl polystyrene,9-(Hydroxymethyl)fluorene-4-carboxamidomethyl polystyrene, HESMpolystyrene, HMBA-AM resin, HMBA-NovaGel™, HMBA-PEGA resin,Hydroxyethylsulfanylmethyl polystyrene, NovaSyn® TG HMBA resin, NovaSyn®TG hydroxy resin, Oxime resin, Aminoethyl photolinker resin,Hydroxyethyl photolinker resins, Hydroxymethyl photolinker resins,3-[4-(Tritylmercapto)phenyl]propionyl AM resin, Mercaptomethylpolystyrene, NovaSyn® TG tritylthiol resin, Thiol 2-chlorotrityl resin,Thiol 4-methoxytrityl resin, (4-Bromophenyl)diisopropylsilyloxymethylpolystyrene, (4-Formylphenyl)diisopropylsilyloxymethyl polystyrene,(4-Trityloxyphenyl)diisopropylsilyloxymethyl polystyrene. Solid supportsalso include TENTAGEL™, HYPOGEL™, JANDAJEL™, AND ARGOGEL™. Other solidsupports include PEGylated polystyrene (polystyrene derivatized withpolyethylene glycol), Tentagel-NH₂ resin, and derivatized Tentagel-NH₂resin (e.g., by treatment with acetyl chloride followed by reductionwith LiAlH₄ to provide Tentagel-NHEt resin). See also the NovabiochemCatalogue 2000 for additional resins and immobilized functional groups.

[0289] Such supports may take any size, shape or form, includingparticulate and non-particulate forms or shapes, spheres, disks,pellets, sheets, plugs, pins, crowns, lanterns, in beaded and non-beadedforms, resins, gels, microspheres, as well as amorphous forms andshapes. Embodiments of particulate supports, include beads, pellets,disks, amorphous particles, or other conventional forms. The solid orsemi-solid supports may be used as single particle, as groups ofparticles, as free flowing particles, and may be packed into columns,tubes or other flow-through devices. In a one embodiment, the diameterof the particulate support is 20-2000 micron, preferably 75-500 micron,more preferably 100-200 micron. As one skilled in the art will readilyrecognize, the scope of the present invention is not limited to thesize, form, or shape of the solid or semi-solid support.

[0290] The linking group component can have a variety of structures. Thelinking group component is one which provides suitable spacing for theactivator portion (—CF₂—SO₂—OX; wherein X is a trisubstituted silyloxy)to interact freely with molecules or reactive components exposed to theactivator portion. The linking group component is preferably 6-50 atomslong, more preferably 8-40 atoms-long, even more preferably 8-30 atomslong, and yet more preferably 8-20 atoms long, thus providing sufficientexposure for the attached activator portion. Additionally, the linkinggroup component, prior to attachment to the support, will have aattaching portion and a longer chain portion. The attaching portion isthat part of the linking group component which can be directly attachedto the solid support. This portion can be attached to the solid supportvia carbon-carbon bonds using, for example, supports having exposed(poly)trifluorochloroethylene moieties, or preferably, by siloxane bonds(using, for example, glass or silicon oxide as the solid support).Siloxane bonds the support are formed in one embodiment via reactions ofattaching portions bearing trichlorosilyl or trialkoxysilyl groups. Theattaching groups will also have a site for attachment of the longerchain portion. For example, groups which are suitable for attachment toa longer chain portion would include amines, hydroxyl, thiol, andcarboxyl.

[0291] One skilled in the art will recognize that many additionalmethods of attaching linkers to solid or semi-solid supports exist. Onemethod uses an amino resin to which an acid-bearing linker is attachedvia conventional techniques. Another method is the use of aryl etherlinkages by coupling a phenol to a Merrifield (or equivalent) resin.

[0292] The longer chain portion can be any of a variety of moleculeswhich are inert to the subsequent conditions used in the activatorreactions described in further detail below. These longer chain portionscan be ethylene glycol oligomers containing 2-14 monomer units, or morepreferably 2-10 monomer units, and even more preferably 2-8 monomerunits; in addition, the longer chain portions can be diamines, diacids,amino acids, peptides, or combinations thereof. In some embodiments, thelonger chain portion also comprises an activator enhancing portion,i.e., a portion that increases the reactivity of the activator relativeto an alkylene or ethylene glycol linking group. More particularly, anactivator enhancing portion is one that provides additional electronwithdrawing character to the activator portion (e.g., the —CF₂—SO₂—OXportion; wherein X is a trisubstituted silyloxy).

[0293] In another group of embodiments, L comprises an activatorenhancing portion selected from the group consisting of:

[0294] wherein Y is a member selected from the group consisting of achemical bond, O, CO, S, and NR¹; Z is a member selected from the groupconsisting of a chemical bond or CO; each R² is independently a memberselected from the group consisting of hydrogen, halogen, (C₁-C₈)alkyl,(C₁-C₈)alkoxy, (C₂-C₈)heteroalkyl, (C₁-C₈)alkylthio, (C₁-C₈)alkylamino,di(C₁-C₈)alkylamino, cyano, nitro and (C₁-C₈)alkylsulfonyl; thesubscript ‘g’ is an integer selected from the group consisting of 0, 1,2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscript ‘i’ is an integer selectedfrom the group consisting of 1, 2, 3, 4, 5, and 6; the subscript ‘j’ isan integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7,8, 9, and 10; the subscript ‘k’ is an integer selected from the groupconsisting of 1, 2, 3, and 4; the subscript ‘m’ is an integer selectedfrom the group consisting of 2 and 3; and the subscript ‘n’ is aninteger selected from the group consisting of 0, 1, 2, 3, and 4. In thegroups described herein as dialkylamino, the alkyl groups can be thesame or different, or can optionally be combined to form a ring havingadditional heteroatoms (e.g., pyrrolidino, morpholino, piperazino).

[0295] In another group of embodiments, the support-bound activatorshave a formula selected from:

[0296] In each of formulae A and B, X is trisubstituted silyloxy; Q isO; Z is a chemical bond or C═O; Y is O-support or NR₁-support wherein R₁is H, (C₁-C₈)alkyl or aryl and the support is a PEG-modified polystyreneor a Merrifield resin; and each R² is as defined more generally above.The subscripts in formulae A and B are as follows: ‘g’ is an integerselected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,and 11; ‘h’ is an integer selected from the group consisting of 1, 2, 3,4, 5, 6, 7, and 8; ‘i’ is an integer selected from the group consistingof 0, 1, 2, 3, 4, 5, 6, 7, and 8; ‘j’ is an integer selected from thegroup consisting of 1, 2, 3, and 4; ‘k’ is an integer selected from thegroup consisting of 1, 2, 3, and 4; ‘m’ is an integer selected from thegroup consisting of 2 and 3; ‘n’ is an integer selected from the groupconsisting of 0, 1, 2, 3, and 4; and ‘q’ is an integer selected from thegroup consisting of 1, and 2.

[0297] In one particular embodiment in formulae A and B, X istrisubstituted silyloxy; Q is O; Z is C═O, Y is NH-support wherein thesupport is a PEG-modified polystyrene; and each R² is H.

[0298] In one embodiment, the trisubstituted silyloxy has the formulaOSiR³R⁴R⁵, wherein, each of R³, R⁴, and R⁵ is independently a memberselected from the group consisting of substituted (C₁-C₈)alkyl,unsubstituted (C₁-C₈)alkyl, substituted (C₁-C₈)alkenyl , unsubstituted(C₁-C₈)alkenyl, substituted aryl, and unsubstituted aryl.

[0299] In another embodiment, each of R³, R⁴, R⁵ is a methyl group; inanother embodiment, each of R³, R⁴ is a methyl group and R⁵ is a t-butylgroup.

[0300] In still other embodiments, each solid or semi-solid supportcomprises a plurality of support-bound silylating groups, with aconcentration of at least 1 mmol support-bound silylating groups pergram of solid or semi-solid support, more preferably, at least 1 μmolsupport-bound silylating groups per gram of solid or semi-solid support,and even more preferably, at least 1 mmol support-bound silylatinggroups per gram of solid or semi-solid support.

[0301] In another embodiment, the silylating support of the presentinvention can be provided in kit form for pre-treatment of testcompounds prior to analysis by a wide range of analytical chemistrytechniques, including gas chromatography and high-performance liquidchromatography. Such a kit could provide the silylating support in theform of a resin or particles packed into a column. The compound to besilylated could then be passed over or through the silylating supportprior to analysis by chromatography.

[0302] See Example 9 below for one illustrative use of the silylatingsupports of the present invention.

[0303] The following examples provide more detailed descriptions ofsynthetic methods used to prepare traceless linkers and activators ofthe present invention. One of skill in the art will appreciate that manyof the methods provided below can be applied to the preparation of otherlinkers and activators. Accordingly, the examples are offered by way ofillustration and not by way of limitation.

EXAMPLES Example 1

[0304] This example illustrates the preparation of a polymer-supportedperfluorosulfonyl fluoride linker (FIG. 1).

[0305] At 0° C., to a stirring solution containing ethyl vinyl ether(600 mg, 8.3 mmol), NaHCO₃ (680 mg, 8.0 mmol), and commercialtetrafluoro-2-(tetrafluoro-2-iodoethoxy)ethanesulfonyl fluoride FIG. 1,Structure 1 (3.5 g, 8.0 mmol) in CH₃CN (8 mL) and H₂O (7 mL) was slowlyadded Na₂S₂O₄ (1.4 g, 8.0 mmol). The reaction mixture was stirred at 5°C. for 50 min. The pH of the reaction mixture was adjusted to 6.2˜7.0 byadding 3.0 N aqueous HCl and the mixture was stirred at 25° C. foranother 20 min. The reaction mixture was extracted with CH₂Cl₂, washedwith water and concentrated under reduced pressure. The oily residue wasdissolved in acetone (38 mL) and the solution was added to a stirringmixture of 2-methyl-butene-2 (36 mL), NaH₂PO₄ (4.0 g, mmol), NaClO₂ (5.0g, mmol) and water (40 mL) at 0-5° C. The reaction mixture was stirredat 5-15° C. for 2 h. The reaction mixture was concentrated under reducedpressure, extracted with ether, washed with brine, dried (MgSO₄) andconcentrated. The oily crude product was purified on a SiO₂ column(MeOH/CHCl₃, 2:98) to give 1.8 g (62%) of the linker FIG. 1, Structure 3as thick oil. ¹HNMR (CDCl₃, δ): 3.17 (t, J=16.8 Hz, CF₂CH₂CO₂H); ¹³C NMR(CDCl₃, δ): 169.54, 36.69, 36.39, 36.09; ¹⁹F NMR (CDCl₃, δ): 121.61(SO₂F), 6.08, 11.51, −36.14, −39.76; MS (ESI) calcd for C₆H₃F₉O₅S357.96, found: 357.0 (M−H)⁻.

[0306] To a stirring solution of the above acid linker FIG. 1, Structure3 (800 mg, 2.24 mmol) and oxalyl chloride (430 μL, 4.8 mmol) in CH₂Cl₂(1.6 mL) was slowly added DMP (18 μL). After the evolution of gasbubbles, the reaction mixture was stirred for another 1 h and thenconcentrated under reduced pressure. The oily product was dissolved inCH₂Cl₂ (5 mL), the solution was added to a commercial TENTAGEL™ NH₂resin (1.08 g, 0.46 mmol) and the resin was cooled in a dry-icecontainer for 10 min. To the resin was slowly addeddiisopropylethylamine (1.2 mL, 7.0 mmol), and the resin was shaken atroom temperature overnight. The beads were washed with CH₂Cl₂ and driedunder vacuum overnight to give resin-bound linker FIG. 1, Structure 4a.

Example 2

[0307] This example illustrates the preparation of difluorosulfonic acidlinker and the resin-bound difluorosulfonic acid (FIG. 2).

[0308] A solution of chloride FIG. 2, Structure 5 (3.8 g, 16.8 mmol) andthiourea (1.3 g, 17 mmol) in EtOH (10 mL) was stirred at 70° C. for 4 hand then cooled to room temperature. A solution of NaOH (1.2 g, 30 mmol)in water (10 mL) was added, and the reaction mixture was stirred at roomtemperature overnight, concentrated under reduced pressure, acidified topH 6, extracted with CH₂Cl₂, washed with water. The crude thiol FIG. 2,Structure 6 was dissolved in CH₂Cl₂ (30 mL), water (30 mL) and aceticacid (2 mL). The solution was cooled to 0-5° C. and Cl₂ gas was bubbledonto the solution for 1 h. The reaction mixture was concentrated,extracted with CH₂Cl₂, washed with cold water, dried (MgSO₄) andconcentrated to give sulfonyl chloride FIG. 2, 7 (4.8 g, 97%/o). ¹H NMR(CDCl₃, δ): 1.60 (s, 9 H), 4.92 (s, 2 H), 7.68 (d, 2 H), 8.38 (d, 2 H);¹³C NMR (CDCl₃, δ): 28.34, 70.52, 81.92, 130.37, 131.44, 134.02, 164.98.

[0309] Et₃N (2.0 g, 19.5 mmol) was added to a solution of FIG. 2, 7 (4.2g, 14 mmol), neopentyl alcohol (2.6 g, 30 mmol) in CH₂Cl₂ (20 mL) at−78° C. The reaction mixture was stirred at room temperature overnight,diluted with cold water, extracted with CH₂Cl₂, washed with water, dried(MgSO₄) and concentrated under reduced pressure to give crude productFIG. 2, 8 as light yellow solid. The crude product was washed with amixture of hexane and ether (4:1) to yield pure FIG. 2, 8 as off-whitepowder (4.3 g, 90%/O). ¹H NMR (CDCl₃, δ): 0.96 (s, 9 H), 1.60 (s, 9 H),3.78 (s, 2 H), 4.40 (s, 2 H), 7.44 (d, 2 H), 8.02 (d, 2 H); ¹³C NMR(CDCl₃, δ): 26.18, 28.36, 32.03, 56.50, 79.83, 81.64, 130.07, 130.74,132.48, 132.87, 165.29.

[0310] To a solution of the benzylic sulfonate ester FIG. 2, 8 (342 mg,1.0 mmol) in anhydrous THF at −78 ° C. was added t-BuLi (620 μL, 1.05mmol) over a period of 2 min, and the mixture was stirred for 30 min at−78° C. A solution of NFSi (341 mg, 1.05 mmol) in THF (0.5 mL) was addeddropwise at −78° C. The mixture was stirred at −78° C. for 1 h. Theprocedure was repeated with t-BuLi (650 μL, 1.10 mmol) and NFSi (357 mg,1.10 mmol). The reaction was quenched with water, extracted with CHCl₃,washed with water, dried (MgSO₄) and concentrated. The crude product waspurified on a SiO₂ column (MeOH /CHCl₃, 2:98) to give pure FIG. 2, 9. Asolution of trifluoroacetic acid (1.8 mL) in CH₂Cl₂ (4 mL) was added toFIG. 2, 9 and the mixture was stirred for 40 min, concentrated to giveFIG. 2, 10 as a white powder (252 mg, 78% from 9). ¹H NMR (CD₃COCD₃, δ):1.02 (s, 9 H), 4.22 (s, 2 H), 7.91 (d, 2 H), 8.26 (d, 2 H).

[0311] Et₃N (30 mg, 0.30 mmol) was added to a solution of FIG. 2, 10 (45mg, 0.14 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′tetramethyluronium hexafluorophosphate (HATU) (60 mg, 0.16 mmol) in DMF(1.5 mL), and the mixture was added to a TentaGel-NH₂ resin (100 mg,0.043 mmol). The resin was shaken at room temperature overnight, washedwith DMF, MeOH and CH₂Cl₂, and dried under vacuum to give resin FIG. 2,11. A solution of LiBr (24 mg, 0.28 mmol) in butane-2-one (1.5 mL) wasadded to the above resin FIG. 2, 11, and the resin was shaken at 70° C.for 72 h. The beads were washed with butane-2-one, DMF and CH₂Cl₂, anddried to give the resin-bound perfluorosulfonic acid FIG. 2, 12.

Example 3

[0312] This example illustrates the use of perfluorosulfonyl fluoridelinker in deoxygenation of various phenols (FIG. 3).

[0313] A mixture of phenol (0.68 mmol), K₂CO₃ (100 mg, 0.72 mmol),resin-bound linker FIG. 3, Structure 4 (80 mg, 0.034 mmol) and DMF (1.0mL) was shaken at room temperature overnight. The resin was washed withwater, DMF and CH₂Cl₂, and was dried under vacuum overnight to giveresin-bound phenol FIG. 3, Structure 13. To the dry resin FIG. 3,Structure 13 were added Pd(OAc)₂ (6.0 mg, mmol),1,3-bis(diphenylphosphino)propane (dppp, 16.0 mg, mmol), DMF (1.2-1.4mL) and a mixture of HCO₂H (180 μL) and Et₃N (460 μL). The mixture wasshaken at 85 ° C. for 120 min. The polymer beads were filtered andwashed with Et₂O. The combined organic phase was washed with aqueousNa₂CO₃ and water, and evaporated to dryness. The residue was dissolvedin Et₂O and eluted through a short column of SiO₂ to remove inorganicresidues. The crude products were purified by preparative TLC to givethe desired products FIG. 3, Structure 14a-1 in >98% purity.

Example 4

[0314] This example illustrates the use of the perfluorosulfonyl halidelinkers of the invention for the cleavage/cross coupling ofpolymer-bound phenols using Suzuki coupling reactions (FIG. 4).

[0315] The resin-bound phenols FIG. 4, Structure 15 were prepared asdescribed in Example 1. A mixture of the dry resin FIG. 4, Structure 15(200 mg, 0.07 mmol), Pd(dppf)Cl₂ (7.2 mg), boronic acid (0.26 mmol) andEt₃N (88 μL, 0.62 mmol) in DMF (1.5-2.0 mL) was placed in a vial anddegassed by blowing N₂ with stirring. The vial was sealed andmagnetically stirred at 90° C. for 8 h. The polymer beads were filteredand washed with Et₂O. The combined organic phase was washed with aqueousNa₂CO₃ solution and water, and evaporated under reduced pressure todryness. The residue was dissolved in Et₂O and eluted through a shortbed of SiO₂ to remove inorganic residues. The crude products werepurified by preparative TLC to give the desired products FIG. 4,Structure 16a-h in >98% purity.

Example 5

[0316] This example illustrates the application of the traceless linkertechnology to the preparation of a library of 10 biaryl compounds, whichfurther illustrate the scope and generality of the linkers (FIG. 5).

[0317] The resin-bound aldehyde FIG. 5, Structure 17 was prepared asdescribed in Example 1. To the dry resin FIG. 5, Structure 17 (100 mg,0.043 mmol) were added amine (0.40 mmol), THF (800 μL), Na(CN)BH₃ (1.0mL) and acetic acid (23 μL). The mixture was shaken at room temperatureovernight. The beads were washed with water, DMF, CH₂Cl₂ and anhydrousTHF, and dried under vacuum overnight to give amine resin FIG. 5,Structure 18. To the dry amine resin FIG. 5, Structure 18 (100 mg, 0.043mmol) were added CH₂Cl₂ (1.2-1.6 mL), acid chloride (0.42 mmol), and theresin was cooled in a dry-ice container for 10 min. To the resin wasslowly added diisopropylethylamine (88 μL, 0.5 mmol), and the resin wasshaken at room temperature overnight. The beads were washed with water,DMF, CH₂Cl₂, and dried under vacuum overnight to give amide resin FIG.5, Structure 19.

[0318] A mixture of the dry resin FIG. 5, Structure 19 (200 mg, 0.07mmol), Pd(dppf)Cl₂ (7.2 mg), boronic acids (0.26 mmol) and Et₃N (88 μL)in DMF (1.0˜1.1 mL) was placed in a vial and degassed by blowing N₂ withstirring. The vial was sealed and magnetically stirred at 90° C. for 8h. The polymer beads were filtered and washed with Et₂O. The combinedorganic phase was washed with aqueous Na₂CO₃ solution and water, andevaporated to dryness. The residue was dissolved in Et₂O and elutedthrough a short bed of SiO₂ to remove inorganic residues. The crudeproducts were purified by preparative TLC to give the desired productsFIG. 5, Structure 20a-i in >98% purity.

Example 6

[0319] This example illustrates the application of perfluorosulfonylfluoride linker to a multi-step synthesis of the therapeutic agent,meclizine (FIG. 6).

[0320] A mixture of 3-methyl-4-hydroxybenzaldehyde (100 mg, 0.72 mmol),K₂CO₃ (100 mg, 0.72 mmol), resin-bound linker FIG. 6, Structure 4 (100mg, 0.043 mmol) and DMF (1.1 mL) was shaken at room temperatureovernight. The beads were washed with water, DMF and CH₂Cl₂, and driedunder vacuum overnight to give resin FIG. 6, Structure 21. To the dryresin FIG. 6, Structure 21 were added 1-(4chlorobenzhydryl)piperazine(128 mg, 0.40 mmol), THF (800 μL), Na(CN)BH₃ (1.0 mL) and acetic acid(23 μL). The mixture was shaken at room temperature overnight. The beadswere washed with water, DME and CH₂Cl₂, and dried under vacuum overnightto give resin FIG. 6, Structure 22.

[0321] To the dry resin FIG. 6, Structure 22 was added Pd(OAc)₂ (8.0 mg,mmol), 1,3-bis(diphenyl-phosphino)propane (dppp, 17.0 mg, mmol), DMF(1.4 mL) and a mixture of HCO₂H (200 μL) and Et₃N (800 μL). The mixturewas shaken at 85° C. for 120 min. The polymer beads were filtered andwashed with Et₂O. The combined organic phase was washed with aqueousNa₂CO₃ solution and water, and evaporated to dryness. The residue wasdissolved in Et₂O and eluted through a short column of Al₂O₃ to removeinorganic residues. The crude products were purified by preparative TLCto give the desired products FIG. 6, Structure 23 in >98% purity.Analytical data of FIG. 6, Structure 23 is identical to that ofauthentic sample.

Example 7

[0322] This example illustrates the preparation of the resin-boundperfluorosulfonic acid (FIG. 7).

[0323] A mixture of resin-bound linker FIG. 7, Structure 4 (500 mg, 0.15mmol), THF (1.0 mL) and 0.6 M LiOH in water (1.2 mL) was shaken at roomtemperature for 2 h. The beads were washed with water and CH₂Cl₂, anddried under vacuum overnight to give resin FIG. 7, Structure 24. ¹⁹F NMR(CDCl₃, δ): −8.00, −43.44.

[0324] To the resin FIG. 6, Structure 24 was added 6 M HCl in water (2.0mL). The mixture was shaken at room temperature for 6 h. The beads werefiltered and washed with CH₂Cl₂, 20% TFA in CH₂Cl₂ and CH₂Cl₂, and driedunder vacuum overnight to give resin FIG. 7, Structure 25. ¹⁹F NMR(CDCl₃, δ): −8.00, −43.44, −6.84, −7.41, −12.55, −42.36, −42.88.

Example 8

[0325] This example illustrates the use of the resin boundperfluorosulfonic acid as a scavenger.

[0326] To a solution of benzylamine (0.125 mmol) in 5 mL of THF is addeddiisopropylethyl amine (0.15 mmol) and benzoylchloride (0.10 mmol). Thereaction mixture is stirred at room temperature for 1 hour or until TLCanalysis shows consumption of the benzoyl chloride. To this mixture isadded perfluorsulfonic acid resin prepared in example 8 (3 g, 0.3 mmol/gloading) and the slurry is gently agitated for 1 hour. The slurry isfiltered and the resin washed with dichloromethane. The combinedfiltrates are combined and the solvent removed under reduced pressure toafford N-benzylbenzamide as a solid.

Example 9

[0327] This example illustrates the use of the perfluorosulfonyl siloxyresin as a silylating resin.

[0328] The free acid resin from example 8 (1 g) is washed withdichloromethane. The resin is treated with a solution of TMS-Cl (10mmol) in 5 mL of dichloromethane and one drop of concentrated sulfuricacid is added. After being gently agitated for 14 h, the resin is washedwith dichloromethane and dried under vacuum.

[0329] To a solution of phenol (0.1 mmol) in dichloromethane is addedthe TMS-resin from above and the resultant slurry is gently agitated for1 h. The resin is filtered away and the filtrate is either directlysubmitted for gas chromatographic analysis or the solvent is removedunder reduced pressure to yield phenoxytrimethylsilane.

[0330] All publications and patent applications cited in thisspecification are herein incorporated by reference as if each individualpublication or patent application were specifically and individuallyindicated to be incorporated by reference. Although the foregoinginvention has been described in some detail by way of illustration andexample for purposes of clarity of understanding, it will be readilyapparent to those of ordinary skill in the art in light of the teachingsof this invention that certain changes and modifications may be madethereto without departing from the spirit or scope of the appendedclaims.

What is claimed is:
 1. A support-bound activator having the formula:

wherein L is a linking group component; X is a member selected from thegroup consisting of F, Cl, OH, and trisubstituted silyloxy; wherein thesupport-bound activator is covalently attached to a solid or semi-solidsupport.
 2. The support-bound activator of claim 1, wherein X is F. 3.The support-bound activator of claim 1, wherein X is Cl.
 4. Thesupport-bound activator of claim 1, wherein X is OH.
 5. Thesupport-bound activator of claim 1, wherein X is trisubstitutedsilyloxy.
 6. The support-bound activator of claim 1, wherein L comprisesan activator enhancing portion selected from the group consisting of:

wherein Y is a member selected from the group consisting of a chemicalbond, O, C(O), S, and NR¹; Z is a member selected from the groupconsisting of a chemical bond and C(O); R¹ is a member selected from thegroup consisting of H and (C₁-C₈)alkyl; each R² is independently amember selected from the group consisting of hydrogen, halogen,(C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₂-C₈)heteroalkyl, (C₁-C₈)alkylthio,(C₁-C₈)alkylamino, di(C₁-C₈)alkylamino, cyano, nitro, and(C₁-C₈)alkylsulfonyl; the subscript g is an integer selected from thegroup consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscripti is an integer selected from the group consisting of 1, 2, 3, 4, 5, and6; the subscript is an integer selected from the group consisting of 0,1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscript k is an integerselected from the group consisting of 1, 2, 3, and 4; the subscript m isan integer selected from the group consisting of 2, and 3; and thesubscript n is an integer selected from the group consisting of 0, 1, 2,3, and
 4. 7. The support-bound activator of claim 1, wherein said solidor semi-solid support is a particulate support.
 8. The support-boundactivator of claim 1, wherein said solid or semi-solid support comprisesa material selected from the group consisting of polystyrene, controlledpore glass, polyacrylamide, poly(ethyleneglycol)monomethyl ether,polyethylene glycol, silica gel, cellulose, acrylic acid graftedpolypropylene, polystyrene modified by polyethylene glycol, andcombinations thereof.
 9. The support-bound activator of claim 1, whereinsaid solid or semi-solid support comprises polystyrene modified bypolyethylene glycol.
 10. An activated support comprising a solid orsemi-solid support; and at least one support-bound activator having theformula:

wherein L is a linking group component; X is a member selected from thegroup consisting of F, Cl, OH, and trisubstituted silyloxy; and whereinthe support-bound activator is covalently attached to the solid orsemi-solid support.
 11. The activated support of claim 10, wherein Lcomprises an activator enhancing portion selected from the groupconsisting of:

wherein Y is a member selected from the group consisting of a chemicalbond, O, C(O), S, and NR¹; Z is a member selected from the groupconsisting of a chemical bond and C(O); R¹ is a member selected from thegroup consisting of H and (C₁-C₈)alkyl; each R² is independently amember selected from the group consisting of hydrogen, halogen,(C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₂-C₈)heteroalkyl, (C₁-C₈)alkylthio,(C₁-C₈)alkylamino, di(C₁-C₈)alkylamino, cyano, nitro, and(C₁-C₈)alkylsulfonyl; the subscript g is an integer selected from thegroup consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscripti is an integer selected from the group consisting of 1, 2, 3, 4, 5, and6; the subscript j is an integer selected from the group consisting of0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscript k is an integerselected from the group consisting of 1, 2, 3, and 4; the subscript m isan integer selected from the group consisting of 2, and 3; and thesubscript n is an integer selected from the group consisting of 0, 1, 2,3, and
 4. 12. The activated support of claim 10, wherein said solid orsemi-solid support is a particulate support.
 13. The activated supportof claim 10, wherein said solid or semi-solid support comprises amaterial selected from the group consisting of polystyrene, controlledpore glass, polyacrylamide, poly(ethyleneglycol)monomethyl ether,polyethylene glycol, silica gel, cellulose, acrylic acid graftedpolypropylene, polystyrene modified by polyethylene glycol, andcombinations thereof.
 14. The activated support of claim 10, whereinsaid solid or semi-solid support comprises polystyrene modified bypolyethylene glycol.
 15. A kit comprising a predetermined amount of theactivated support of claim
 10. 16. A support-activated target comprisinga solid or semi-solid support; an activating group covalently attachedto the solid or semi-solid support, wherein the activating group has theformula:

and wherein L is a linking group component; and a target groupcovalently attached to the activating group; wherein the target groupcan be cleaved from the activating group by a nucleophile.
 17. Thesupport-activated target of claim 16, wherein L comprises an activatorenhancing portion selected from the group consisting of:

wherein Y is a member selected from the group consisting of a chemicalbond, O, C(O), S, and NR¹; Z is a member selected from the groupconsisting of a chemical bond and C(O); R¹ is a member selected from thegroup consisting of H and (C₁-C₈)alkyl; each R² is independently amember selected from the group consisting of hydrogen, halogen,(C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₂-C₈)heteroalkyl, (C₁-C₈)alkylthio,(C₁-C₈)alkylamino, di(C₁-C₈)alkylamino, cyano, nitro, and(C₁-C₈)alkylsulfonyl; the subscript g is an integer selected from thegroup consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscripti is an integer selected from the group consisting of 1, 2, 3, 4, 5, and6; the subscript j is an integer selected from the group consisting of0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscript k is an integerselected from the group consisting of 1, 2, 3, and 4; the subscript m isan integer selected from the group consisting of 2, and 3; and thesubscript n is an integer selected from the group consisting of 0, 1, 2,3, and
 4. 18. The support-activated target of claim 16, wherein saidsolid or semi-solid support is a particulate support.
 19. Thesupport-activated target of claim 16, wherein said solid or semi-solidsupport is composed of a material selected from the group consisting ofpolystyrene, controlled pore glass, polyacrylamide,poly(ethyleneglycol)monomethyl ether, polyethylene glycol, silica gel,cellulose, acrylic acid grafted polypropylene, polystyrene modified bypolyethylene glycol, and combinations thereof.
 20. The support-activatedtarget of claim 16, wherein said solid or semi-solid support comprisespolystyrene modified by polyethylene glycol.
 21. A library ofsupport-activated targets comprising a plurality of support-activatedtarget members, wherein each support-activated target member furthercomprises a solid or semi-solid support; an activating group covalentlyattached to the solid or semi-solid support, wherein the activatinggroup has the formula:

wherein L is an linking group component; and a target group covalentlyattached to the activating group; wherein the target group of at leastone support-activated target member in the library is different from thetarget group of at least one other support-activated target member inthe library.
 22. The library of support-activated targets of claim 21,wherein L comprises an activator enhancing portion selected from thegroup consisting of:

wherein Y is a member selected from the group consisting of a chemicalbond, O,C(O), S, and NR¹; Z is a member selected from the groupconsisting of a chemical bond and C(O); R¹ is a member selected from thegroup consisting of H and (C₁-C₈)alkyl; each R² is independently amember selected from the group consisting of hydrogen, halogen,(C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₂-C₈)heteroalkyl, (C₁C-₈)alkylthio,(C₁-C₈)alkylamino, di(C₁-C₈)alkylamino, cyano, nitro, and(C₁-C₈)alkylsulfonyl; the subscript g is an integer selected from thegroup consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscripti is an integer selected from the group consisting of 1, 2, 3, 4, 5, and6; the subscript j is an integer selected from the group consisting of0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscript k is an integerselected from the group consisting of 1, 2, 3, and 4; the subscript m isan integer selected from the group consisting of 2, and 3; and thesubscript n is an integer selected from the group consisting of 0, 1, 2,3, and
 4. 23. The library of support-activated targets of claim 21,wherein said solid or semi-solid support is a particulate support. 24.The library of support-activated targets of claim 21, wherein said solidor semi-solid support is composed of a material selected from the groupconsisting of polystyrene, controlled pore glass, polyacrylamide,poly(ethyleneglycol)monomethyl ether, polyethylene glycol, silica gel,cellulose, acrylic acid grafted polypropylene, polystyrene modified bypolyethylene glycol, and combinations thereof.
 25. The library ofsupport-activated targets of claim 21, wherein said solid or semi-solidsupport comprises polystyrene modified by polyethylene glycol.
 26. Astrongly acidic support comprising a solid or semi-solid support; and atleast one support-bound strongly acidic group having the formula:

wherein L is a linking group component; and X is OH; wherein thesupport-bound strongly acidic group is covalently attached to the solidor semi-solid support.
 27. The strongly acidic support of claim 26,wherein L comprises an activator enhancing portion selected from thegroup consisting of:

wherein Y is a member selected from the group consisting of a chemicalbond, O, C(O), S, and NR¹; Z is a member selected from the groupconsisting of a chemical bond and C(O); R¹ is a member selected from thegroup consisting of H and (C₁-C₈)alkyl; each R² is independently amember selected from the group consisting of hydrogen, halogen,(C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₂-C₈)heteroalkyl, (C₁-C₈)alkylthio,(C₁-C₈)alkylamino, di(C₁-C₈)alkylamino, cyano, nitro, and(C₁-C₈)alkylsulfonyl; the subscript g is an integer selected from thegroup consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscripti is an integer selected from the group consisting of 1, 2, 3, 4, 5, and6; the subscript j is an integer selected from the group consisting of0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscript k is an integerselected from the group consisting of 1, 2, 3, and 4; the subscript m isan integer selected from the group consisting of 2, and 3; and thesubscript n is an integer selected from the group consisting of 0, 1, 2,3, and
 4. 28. The strongly acidic support of claim 26, wherein saidsolid or semi-solid support is a particulate support.
 29. The stronglyacidic support of claim 26, wherein said solid or semi-solid support iscomposed of a material selected from the group consisting ofpolystyrene, controlled pore glass, polyacrylamide,poly(ethyleneglycol)monomethyl ether, polyethylene glycol, silica gel,cellulose, acrylic acid grafted polypropylene, polystyrene modified bypolyethylene glycol, and combinations thereof.
 30. The strongly acidicsupport of claim 26, wherein said solid or semi-solid support comprisespolystyrene modified by polyethylene glycol.
 31. A silylating supportcomprising a solid or semi-solid support; and at least one support-boundsilylating group having the formula:

wherein L is a linking group component; and X is a trisubstitutedsilyloxy; wherein the support-bound silylating group is covalentlyattached to the solid or semi-solid support.
 32. The silylating supportof claim 31, wherein L comprises an activator enhancing portion selectedfrom the group consisting of:

wherein Y is a member selected from the group consisting of a chemicalbond, O, C(O), S, and NR¹; Z is a member selected from the groupconsisting of a chemical bond and C(O); R¹ is a member selected from thegroup consisting of H and (C₁-C₈)alkyl; each R² is independently amember selected from the group consisting of hydrogen, halogen,(C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₂-C₈)heteroalkyl, (C₁-C₈)alkylthio,(C₁-C₈)alkylamino, di(C₁-C₈)alkylamino, cyano, nitro, and(C₁-C₈)alkylsulfonyl; the subscript g is an integer selected from thegroup consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscripti is an integer selected from the group consisting of 1, 2, 3, 4, 5, and6; the subscript j is an integer selected from the group consisting of0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscript k is an integerselected from the group consisting of 1, 2, 3, and 4; the subscript m isan integer selected from the group consisting of 2, and 3; and thesubscript n is an integer selected from the group consisting of 0, 1, 2,3, and
 4. 33. The silylating support of claim 31, wherein said solid orsemi-solid support is a particulate support.
 34. The silylating supportof claim 31, wherein said solid or semi-solid support is composed of amaterial selected from the group consisting of polystyrene, controlledpore glass, polyacrylamide, poly(ethyleneglycol)monomethyl ether,polyethylene glycol, silica gel, cellulose, acrylic acid graftedpolypropylene, polystyrene modified by polyethylene glycol, andcombinations thereof.
 35. The silylating support of claim 31, whereinsaid solid or semi-solid support comprises polystyrene modified bypolyethylene glycol.
 36. The silylating support of claim 31, wherein Xis a tri(C₁-C₈) silyloxy.
 37. The silylating support of claim 31,wherein X is a member selected from the group consisting of OSi(CH₃)₃and OSi(CH₃)₂t-Bu.
 38. A kit for silylating a target comprising apredetermined amount of the silylating support of claim
 31. 39. A methodfor covalently attaching a nucleophile to a compound having a hydroxygroup or an enolizable ketone, said method comprising, (a) contactingsaid compound with a support-bound activator of claim 1, to form anactivated complex; and (b) contacting said activated complex with areagent, said reagent comprising a nucleophile; wherein said contactingcomprises conditions sufficient to covalently attach said nucleophile tosaid compound.
 40. A method in accordance with claim 39 wherein saidconditions sufficient to covalently attach said nucleophile to saidcompound includes addition of a transition metal catalyst.
 41. A methodin accordance with claim 39 wherein said reagent is a member selectedfrom the group consisting of an organostannane compound, anorganolithium compound, an organozinc compound, an organoboron compound,an organoaluminum compound, a Grignard reagent, an organosiliconcompound, an organocopper compound, a thiol, a dialkylphosphite, anamine, a metal halide, and a halogen.
 42. A method in accordance withclaim 39, wherein said nucleophile is a member selected from the groupconsisting of an amine, a halogen anion, an aryl moiety, an alkylmoiety, and a hydride.
 43. A method in accordance with claim 39, whereinsaid nucleophile is hydride.
 44. A method in accordance with claim 39,wherein said reagent is an aryl boronic acid.
 45. A method in accordancewith claim 39, wherein said nucleophile is an ¹⁸F anion.
 46. A method inaccordance with claim 39, wherein said nucleophile is an ¹¹CH₃ anion.47. A linker reagent having the formula:

wherein L is a linking group component; and A is an attaching group. 48.A linker reagent of claim 47, wherein said attaching group is a memberselected from the group consisting of NH₂, NHR, CO₂H, CO₂R, COCl, OH,SH, and protected forms thereof, wherein each R is independently amember selected from the group consisting of substituted (C₁-C₈)alkyl,unsubstituted (C₁-C₈)alkyl, substituted aryl, and unsubstituted aryl.49. A linker reagent of claim 47, wherein said attaching group is CO₂H.50. A linker reagent of claim 47, wherein said attaching group is COCl.51. A linker reagent of claim 47, wherein L is a member selected fromthe group consisting of:

wherein Y is a member selected from the group consisting of a chemicalbond, O, C(O), S, and NR¹; Z is a member selected from the groupconsisting of a chemical bond and C(O); R¹ is a member selected from thegroup consisting of H and (C₁-C₈)alkyl; each R² is independently amember selected from the group consisting of hydrogen, halogen,(C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₂-C₈)heteroalkyl, (C₁-C₈)alkylthio,(C₁-C₈)alkylamino, di(C₁-C₈)alkylamino, cyano, nitro, and(C₁-C₈)alkylsulfonyl; the subscript g is an integer selected from thegroup consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscripti is an integer selected from the group consisting of 1, 2, 3, 4, 5, and6; the subscript j is an integer selected from the group consisting of0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; the subscript k is an integerselected from the group consisting of 1, 2, 3, and 4; the subscript m isan integer selected from the group consisting of 2, and 3; and thesubscript n is an integer selected from the group consisting of 0, 1, 2,3, and
 4. 52. A linker reagent in accordance with claim 47, having theformula: HO₂C—(CH₂)_(j)—(CF₂CF₂)_(k)O—(CF₂)₂—SO₂F wherein the subscriptj is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5,6, 7, 8, 9, and 10; and the subscript k is an integer selected from thegroup consisting of 1, 2, 3, and
 4. 53. A linker reagent in accordancewith claim 47, wherein the subscript j is 1 and the subscript k is 1.54. A linker reagent in accordance with claim 47, having the formula:HO₂C—(CH₂)_(g)—(CF₂)_(i)—SO₂F wherein the subscript g is an integerselected from the group consisting of 3, 4, 5, and 6; and the subscripti is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5,6, 7, 8, 9, and 10.